Alzheimer's Disease and Advanced Drug Delivery Strategies

Alzheimer's Disease and Advanced Drug Delivery Strategies compiles under a single volume the most recent advances in drug delivery to the brain as related to AD treatment.

The editors recruited scientists from around the world to produce high quality chapters covering not only nanotechnological approaches, but also microsphere, niosomes, and liposomes. Among the topics covered are synthetic molecules, nobiletin, nose to brain delivery, natural biomaterials, cationic nanoformulations, dendrimers, microbubbles, and more.

Alzheimer's Disease and Advanced Drug Delivery Strategies is a complete reference for academic and corporate pharma researchers investigating targeted drug delivery to the brain. Medical & Health Sciences researchers would also benefit from understanding the strategies compiled under this volume.

• Provides insights into how advanced drug delivery systems can be effectively used for the management of Alzheimer’s disease
• Includes the most recent information on diagnostic methods and treatment strategies using controlled drug delivery systems
• Covers recent perspectives and challenges towards the management and diagnosis of Alzheimer’s Disease

• Language: English
• Publisher: Academic Press
• Release date: Nov 30, 2023
• ISBN: 9780443132063

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Chapter 1: Etiology, pathogenesis of Alzheimer's disease and amyloid beta hypothesis

Sarika Maruti Kamblea, Kalpesh Ramdas Patilb, and Aman B. Upaganlawarc     aDepartment of Pharmacology, Sandip Institute of Pharmaceutical Sciences, Nashik, Maharashtra, India     bDepartment of Pharmacology, R.C. Patel Institute of Pharmaceutical Education and Research, Dhule, Maharashtra, India     cDepartment of Pharmacology, SNJBs SSDJ College of Pharmacy, Nashik, Maharashtra, India

Abstract

Alzheimer disease (AD) is advanced neurodegenerative condition characterized by dementia, accounting for an estimated 60%–70% of cases worldwide. AD is progressive disease affecting an elderly patient in the age of 60–65 years. It is leading cause of death in this age group. Epidemiologically, it is estimate that by 2050 the global burden of AD may rise in developing countries and may reach up to 107 million. Clinically, AD is classified in several stages (I to VI) and histopathologically in four stages according to the extent of disease progression. AD pathogenesis includes the amyloid cascade theory based on the deposition of amyloid beta (Aβ) plaques and abnormal tau tangles in the brain. Neuritic plaques are microscopic lesions enclosed by atypical axonal endings and extracellular Aβ peptide deposition. Aβ is consequent from a bulky protein called amyloid precursor protein (APP). The Aβ is cleaved product of amyloid precursor protein (APP) through the proteases like α, β and γ-secretase. Lack of α-secretase elevates the possibility of Aβ peptide formation. Irrespective of biological context, AD has robust genetic correlation with APP, presenilin 1, presenilin 2 and Apolipoprotein E genes. Modulations in such genes are indirectly related with development of plaques, neuroinflammation, neuronal damage and dementia. Several studies correlated the dysregulation of central and peripheral immune system with progression of AD.

Keywords

β-amyloid hypothesis; Alzheimer's disease; Alzheimer's disease genetics; Etiology of Alzheimer's disease; Pathogenesis of Alzheimer's disease

1. Introduction

The group of prevalent and disabling neurodegenerative ailments include Alzheimer's, Huntington's and Parkinson's disease. Additionally, neurodegeneration is the primary cause of multiple sclerosis's irreversible neurological impairment [1]. It is anticipated that by the end of the next 28 years, there would be 152 million patients, up from the present 50 million [2]. With an estimated 60%–70% of cases globally, Alzheimer's Disease (AD) is frequent source of dementia with predicted prevalence of 10% in individuals under the age of 65; however, it surges to 32% in population of age above 85 years, when its yearly incidence is anticipated to be 6.48%. The verbal, visuospatial, and executive domains of cognition gradually deteriorate in AD patients, as well as memory. Amyloid beta (Aβ) plaques and tau tangles (TTs) are pathological AD indicators [3]. Neuronal loss, the progressive buildup of neurofibrillary tangles (NFTs) along with presence of amyloid fibers in neuritic plaques and blood vessel walls are the hallmarks of AD. Even though amyloid pathology and NFT are both typical characteristics of AD, it is unclear how these two diseases are related. However, both illnesses are the ultimate outcome of protein aggregation: Aβ becomes fibrillated and produces amyloid plaques, whereas tau get aggregated following hyperphosphorylation and causes NFTs. Numerous studies have demonstrated a connection between these two clinical AD indicators and an attack via free radicals, or oxidative stress. The amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes are situated on chromosome 21, 14 and 1, individually. Additionally, the apolipoprotein E4 gene's epsilon 4 allele (APOE ε4) on chromosome 19 is connected with improved danger of AD [4].

2. Etiology of Alzheimer's disease

As depicted in Fig. 1.1; cardiovascular diseases related cerebral ischemic injury, aging, genetic predisposal, and oxidative stress are the main etiology for the advancement of neurodegenerative disorders like AD.

The AD is triggered through several central nervous system (CNS) insults, including brain trauma. Increased cytokine production and inflammation are brought on by these insults [4]. At first glance, AD and cerebral ischemic injury could seem to be two quite different CNS conditions. Nevertheless, it has been shown that both start at parallel predispositions and share path that culminates in cell death. There are similarities between the pathophysiology of brain ischemia and AD which have recently highlighted, and such resemblance contributes for buildup of Aβ peptide and consequent neuronal toxicity [5]. The relationship between trauma brain injury (TBI) and AD has been confirmed by the identification of conditions that resemble AD, such as abnormal tau aggregation and buildup after lesions in animal models and TBI survivors [6]. In general, the term neuro-inflammation refers to an inflammatory reaction inside central nervous system (CNS) triggered by many pathogenic events, including infection, trauma, ischemia, and toxins. Neuro-inflammation is one of the causes of AD [3].

Fig. 1.1  Etiology of Alzheimer's disease.

The genesis of AD may also be related to cerebral ischemia, according to growing data. Most cases of AD arise above age 65, with younger people rarely being affected. The brain's volume and weight are reduced because of this irreversible and extremely complicated process. Additionally, it causes the ventricles to grow in some regions of the brain and lose synapses. In addition, a number of diseases exist, including abnormal cholesterol homeostasis and hyperglycemia [2]. Together with apolipoprotein E (APOE), bridging integrator 1 (BIN1) gene is noted primary threat factor for AD [7–9].

When the brain is removed during an autopsy, the average weight noticed is 1200–1400 g. Brain weight start decline between the 45–50 years of age and achieve lowest weight after 86 years. The aging human brain has Aβ plaques and NFTs, the well-known pathological markers of AD, even in those who do not have dementia [10].

Reactive oxygen species (ROS) are defined as oxygen free radicals like superoxide (O2.-), hydroxyl ion (.OH), as well as nonradical derived from hydrogen peroxide (H2O2), singlet oxygen (¹O2) and hypochlorous acid (HOCl). The AD patients have modified Fe metabolism in brain [11]. AD patient's brain shows presence of many macromolecules derived from oxidative stress. Additionally, the AD pathology is believed to involve the depletion of the antioxidant enzymes like glutathione reductase and superoxide dismutase [12]. Acetylcholine deficiency in AD is linked with altered anticholinesterase (AChE) activity. ROS-induced oxidative stress caused by a disparity in redox metal homeostasis is vital in AD etiology. The AD brain has been found to include oxidized DNA, hydroxyl radical adducts, lipid peroxides, advanced glycation end products, and other oxidative stress key indicators [13].

3. Pathogenesis of Alzheimer's disease

Pathogenesis of AD is represented by two pathways; one is based on amyloid deposition and second is based on NFT changes.

3.1. Amyloid deposition neuropathogenesis

Numerous variations in size and form can be seen in the plaque-like deposits. Most of them continue to be free of pathologically altered argyrophilic nerve cell processes and do not exhibit neuropil deformities or glial cell accumulations. The nerve cells located within the deposits seem to be essentially unaltered [14]. Therefore, it is important to distinguish between amyloid deposits and neuritic plaques [15]. Early stages accumulation of amyloid deposition shows substantial variation as depicted in Fig. 1.2. The differentiation of only three stages possible such as Stage A, B and C.

Fig. 1.2  Amyloid deposition in neuropathogenesis of Alzheimer's disease.

Stage A: The isocortex is where low density amyloid deposits emerge initially, notably at basal regions of frontal, temporal, and occipital lobes. There are still no amyloid deposits in the hippocampus formation. The presubiculum's parvocellular layer, as well as the entorhinal layers, Pre-β and Pre-γ, exhibit faintly stained amyloid bands that frequently have hazy borders.

Stage B: Practically all isocortical association regions have medium levels of amyloid deposits. Only the primary motor field and the primary sensory sections do not have any deposits or have very little of them. There are sporadic amyloid deposits in the belt regions and somewhat extensive parts of the frontal and parietal lobes adjacent to central region. A glial layer I-VI shows globular amyloid depositions at varied intensity [16].

Stage C: Stage C reveals densely packed deposits in almost all isocortical regions, which essentially stay structured in their laminar distribution. So Stage C is mostly defined by amyloid depositions in primary isocortical regions [15].

3.2. Neurofibrillary changes based neuropathogenesis

Neurofibrillary changes-based neuropathology can be characterized by stages from I to VI as shown in Fig. 1.3.

Stage I: The transentorhinal area is accountable for the mildest damage. Between entorhinal area and adjacent temporal isocortex, there is complicated transition zone. The Pre-α area travels across external cortical layers and makes it as unique area. Pre-α neurons progressively develop as pyramidal cells during this course. There are just a few of these modifications throughout Stage I. Additionally, a few isolated NFTs might appear in the right entorhinal layer [17–19].

Stage II: This is advanced stage that shows involvement of NFT and neuropil threads (NT) in transentorhinal Pre-α. When they get close to the correct entorhinal Pre-α, their density somewhat reduces. Trace amounts of NFT are present in the hippocampus sector CA1, namely in its wedge-structure extremity overlaying subiculum. Antero-dorsal nucleus of the thalamus and magnocellular forebrain nuclei are either unaffected or undergo relatively minor alterations. In isocortical association regions, solitary NFTs might occasionally be seen.

Stage III: This stage shows participation of Pre-α layer in transentorhinal and entorhinal regions. An NFT is present in many projection neurons in Pre-α. These cells' many dendrites contain NT, which typically enables understanding of the size of the dendritic tree. Originally in 19th century, ghost tangles are detected in NFT. The isocortex either exhibits essentially no alterations or relatively minor ones. Some people have scattered NFT and NT at basal regions of third and fifth layers of frontal, temporal, and occipital association area. Others just show minor randomly spaced NP at layer-III [16].

Stage IV: Pre-α layer is especially seriously affected at the fourth step. Both transentorhinal and entorhinal brain areas have a lot of ghost tangles. Also playing a significant role are the layers Pri-α and Pre-β. Additionally to CA1 a small affection with tangles of multipolar CA4-nerve cells near fascia dentata is seen. Claustrum's basal parts show just minor damage. Large neurons found in the putamen's and the accumbens nucleus' basal regions may also exhibit NFT. More severely impacted nuclei include those in the reuniens and tuberomammillary regions [16,20,21].

Fig. 1.3  Neurofibrillary changes based neuropathogenesis of Alzheimer's disease.

Stages V: With many ghost tangles in layer Pre-α, Stage V exhibits dramatic alterations. Due to the extensive NT, deep layer Pri-α is badly affected which looks like band. Moreover, Pre-β and Pre-γ layers are noticeably impacted. Both parasubiculum and transsubiculum's parvocellular layers exhibit many NT and tiny NFT. Stage V's primary characteristic is, however, the isocortex's significant impairment. When the isocortex is minimally impacted, alterations are limited to retrosplenial area, the medial facies' basal regions, and complete inferior facies of temporal and occipital lobes. Following are the orbitofrontal cortex and insula's antero-basal regions, in situations when the isocortex is more severely compromised. Additionally, a few NFT and NT can be seen in substantia nigra and hypothalamus.

Stage VI: All these modifications are more noticeable in stage VI. Pre and Pri α layers show a significant loss of nerve cells accompanied by many ghost tangles. Yet these tangles are occasionally degenerated and restored by glial cells. Numerous tiny NFT and a thick web of NT are seen in parasubiculum and transsubiculum. Stage V and stage VI may be distinguished more easily because of the fascia dentata. At top half of stratum radiatum (SR) and stratum oriens (SOs), CA1 is distinguished by a significant loss of neuronal cells, the existence of many ghost tangles, and distinct NT stripes. A considerable neuronal cell loss, presence of many ghost tangles, and unique NT stripes at top half of SR and SO separate CA1 from other brain regions [19,20].

4. Diagnosis of AD

National Institute on Aging-Association Alzheimer's (NIA-AA) revised the diagnostic criteria for mild cognitive impairment and stages of AD linked dementia in 2011 based on the original 1984 diagnostic criteria [22,23]. Patients are required to submit to testing including MRIs as well as neurological and pathological examinations. According to several researches, neurologic issues and vitamin B12 deficiency pose a significant risk for the condition [2]. Recently, a noninvasive imaging test was developed to increase an accuracy of AD diagnosis.

Patients receives an injection of radiolabeled tracer agent, and then subjected to customized PET scan to look for Aβ plaques in living brain. However, because amyloid PET imaging is still expensive for most patients, its usage in clinical settings is still restricted. Many individuals who receive amyloid PET imaging right now do so as a requirement for taking part in clinical studies [23,24]. The diagnosis of AD is made when a biopsy or autopsy demonstrates the disease histopathologically. MRI atrophy and tau measurements are two examples of neuronal damage markers for AD. A more intrusive but less expensive test involves checking the CSF for the presence of Amyloid-β, the hyperphosphorylated tau peptide, and total tau protein [25]. Serum microRNA profile screen, another blood test with potential, showed reliability and validity in smaller studies [26]. However, no distinction in the diagnostic efficacy between CSF amyloid-β, p-tau ratio and amyloid PET imaging biomarkers have revealed, which indicates dependability of optimum test on accessibility, cost, and preference [27].

5. Amyloid beta protein hypothesis

AD is common irreversible neurodegenerative ailment of advanced age [28]. This brain disorder is characterized by the slow but progressive loss of brain activities [29]. It is linked with the degeneration of brain cells that results in dementia, represented by impaired cognition and routine activities [30]. The prototypical AD is presented as amnestic cognitive impairment [31]. AD is biologically manifested as the presence of plaques produced due to the deposition of fibrils consisting of β-amyloid (Aβ). The main pathological issue in AD is conversion of Aβ into neurotoxic oligomer, fibrils, and plaques [28].

Presence of distinctive brain lesions emphasizes on Aβ involvement in AD development [32]. Evidently, so-called amyloid cascade hypothesis, formerly suggested in 1990s by Hardy and Higgins [33]. Accumulating research evidences shows involvement of Aβ in the development of AD and project Aβ as therapeutic target [34]. Since Aβ production is a consequence of usual neuronal activity, it is presumably suited to sustain synaptic homeostasis [35]. In CNS, Aβ exhibit concentration dependent dual role. Physiological secretion of Aβ at lower concentration (pM) promotes neurogenesis, synaptic plasticity, neurosurvival, memory and antioxidant function, whereas reduces the oxidative stress. However, excessive Aβ generation (nM) leads to neuronal damage, impaired neuronal function and neurotoxicity triggering neuronal death [36]. The disparity between clearance and accumulation of Aβ generates tau containing neurofibrillary tangles [37,38]. Amyloid hypothesis suggests that Aβ initiates a cascade that impacts synapses and eventually neurons, leading to pathological development of Aβ plagues, tau tangles, synaptic loss, neuronal degradation and dementia [39]. Aβ monomer aggregation causes transition of oligomers from small to large molecular weight oligomers, mature amyloid fibrils and finally senile plaques which are resistant to proteolytic digestion, and chemical denaturation, hence declined clearance [36].

The APP has vital role in AD, due to influential role of a proteolytic fragment (Aβ) derived from APP [32]. Aβ is obtained from amyloid precursor protein (APP), consisting of many amino acids (695–770) that rests in and traverses the cell membrane [40]. APP is Type-I membrane embedded glycoprotein located in CNS and linked to axonal transport and neuronal development [28,41,42]. APP is constitutively cleaved by the specific proteases namely α, β, and γ-secretase during APP processing and maturation. The pathophysiological consequences of the APP cleavage are governed by the involvement of type of proteases. The APP cleavage through α, and γ-secretase has physiological significance exhibited as nonamyloidogenic pathway. However, APP processing through β, and γ-secretase is regarded as pathological trail referred as amyloidogenic pathway. Nonamyloidogenic pathway known as constitutive secretary pathway involves APP cleavage through α-secretase forms soluble APP ectodomain, sAPPα and intracellular membrane bound C-terminal fragment-α or C-83. Subsequently, γ-secretase proceeds to cleave the CTF-83 to yield an extracellular peptide (p3) and APP intracellular domain (AICD). Amyloidogenic pathway shows involvement of β-secretase producing extracellular APP ectodomain, sAPPβ and C-terminal fragment-β or C-99. β-secretase or β-site APP cleaving enzyme (BACE1) or Asp-2 or memapsin-2 is a single transmembrane aspartyl protease which produces of Aβ N-terminus. However, APP cleavage at other β-secretase cleavage site produces alternative fragment, CTF-89 [43]. Further involvement of γ-secretase produces Aβ and AICD [34]. C-terminal fragments of APP are cleaved by bulky complex, γ-secretase. This complex comprises of presenilins (PSs), nicastrin, anterior pharynx defective 1 (APH-1), and presenilin enhancer 2 (PEN-2) [44]. In healthy subjects, Aβ cleaved from APP through β, and γ-secretase is transported extracellularly, where it is quickly cleared or destroyed. The reduced metabolic capacity to breakdown Aβ in pathological situations or advanced age leads to the Aβ peptide accumulation [41].

The Aβ formed because of cleavage of C99 by γ-secretase comprises of short-length peptides. Among several isoforms of Aβ peptide, commonly evident isoforms in the AD pathology are Aβ40 and Aβ42 [42]. Aβ42 is the more hydrophobic isoform of Aβ than the Aβ40 [41]. Generally, Aβ40 peptides are antiamyloidogenic and less hazardous than Aβ42 due to its ability to inhibit Aβ 42 oligomerization. However, propensity of Aβ42 peptides to aggregate and form fibrils makes Aβ42 toxic than Aβ40 [32,45]. Mostly, Aβ1-40 peptide is formed, but longer and noxious isoform, Aβ1-42, can also be formed [42]. Aberrant APP processing through the genetic mutation causes elevated Aβ levels and excessive generation of Aβ42 or Aβ43 over the Aβ 40 peptides [39]. Aβ fibril formation is triggered by elevated Aβ42 level or rise in Aβ42 to Aβ40 ratio. The subsequent senile plaque causes neurotoxicity and tau pathology, which results in neuronal death [41]. The amyloid beta hypothesis is represented as Fig. 1.4.

Fig. 1.4   Events in amyloid beta hypothesis of Alzheimer's disease. AICD, Amyloid precursor protein intracellular domain; APP, Amyloid precursor protein; CTF-83, C-terminal fragment-83; CTF-99, C-terminal fragment-99; p3, Extracellular peptide 3; sAPPα, Soluble amyloid precursor protein alpha; sAPPβ, Soluble amyloid precursor protein beta.

6. Consequences of amyloid beta (Aβ) formation

An interaction of Aβ oligomers with variety of postsynaptic receptors arbitrates neuronal damage in AD. The intracellular Aβ is critical to AD pathophysiology. Aβ internalization is mediated by several receptors including Alpha 7 nicotinic acetylcholine receptor (α7nAChR) [46]. The α7nAChR is a ligand-gated ion channel found in specific brain regions and involved in cognition [37]. Increased expression of α7nAChR is noted in the neurons comprising intracellular Aβ peptide. This α7nAChRs upregulation by the Aβ causes induction of tau phosphorylation through activated tau kinases, c-Jun N-terminal Kinase-1 (JNK-1) and Extracellular signal-regulated kinase (ERK) [37,47]. Lysosome, mitochondria, and endoplasmic reticulum can take up intracellular Aβ to produce toxic Aβ oligomers, which can damage organelles and cause neuronal cell destruction or apoptosis [37,48]. The α7nAChR mediated postsynaptic signaling trail is blocked following the binding of Aβ to α7nAChR. Subsequent interruption of constitutive α7nAChR ligand-binding activity leads to dysfunction of neuron and defects in cognition [37]. Intracellular Aβ1-42 might expedite an emergence amyloid plaques [49].

A cell surface protein, cellular prion protein (PrPC) is overexpressed in the several tissues including CNS. PrPC has role in the development of neurodegenerative or prion disorders like AD [50,51]. Recently, Aβ oligomers exhibited their ability to form complexes with PrPC. The Aβ-PrPc complex is involved in the initiation and advancement of AD. When Aβ binds to the PrPC, it initiates mGluR5-dependent signaling events [52]. During normal physiology, the excitatory neurotransmitter glutamate mediates memory and learning. Impaired glutamatergic signaling has also been linked to several neurodegenerative diseases like AD [53]. The metabotropic glutamate receptors (mGluR) support the formation of Aβ-PrPc complex and triggers the mGluR5-dependent neurotoxic signaling pathway. The consequences of Aβ- PrPc-mGluR5 interaction includes activation of protein tyrosine kinase Fyn, intracellular calcium release, and ERK1/2 phosphorylation leading to synaptic breakdown and loss [54]. Additionally, Aβ-PrPc interaction also modifies NMDA receptor activity and triggers downstream secondary messenger cascade involving calcium influx, excitotoxicity and synaptic loss [52]. Activation of NR2B domain of NMDA also involves the stimulation of MAPK and impairment of cAMP-response element binding protein (CREB) [53].

The p75 neurotrophin receptor (p75NTR) represents tumor necrosis factor (TNF) receptor family and transmembrane glycoprotein having affinity for various neurotrophins that support synaptic plasticity and neuronal survival. The p75NTR functions as receptor for Aβ [55]. The Aβ can causes cytotoxicity and apoptosis via p75-mediated pathway which includes downstream stimulation of intracellular p75 death domain and phosphorylation of JNK [53]. Neuroligins (NLs) are postsynaptic transmembrane cell-adhesion molecules having extracellular cholinesterase like domain. Interaction of Aβ with this domain of NL promote the Aβ oligomer generation and ultimately reduces synaptic connectivity [53,56].

7. Genetic factors responsible for the Alzheimer's disease

Prevalent reason of neurodegenerative disorders among aged individual is Alzheimer disease (AD) [57,58]. The AD is categories into early or late onset disease. Early onset AD (EOAD) represents less prevalent form (approximately 5%) of diseases that occurs before to the age of 60 years. However, the most prevalent AD type that occurs later 60 years of age is referred as late onset AD (LOAD) [57–59]. Autosomal dominant AD (ADAD) is characterized as pathological confirmation of a prevalent hereditary form of AD [60]. Familial AD and EOAD may include ADAD, but they could also encompass AD from nondominant origins like apolipoprotein E4 allele or sporadic AD [60]. APP, PSEN1, and PSEN2 gene mutations are linked with development of early onset familial AD (EOAD) [57,60].

The EOAD is categorized as AD1, AD2 and AD3 subsets, depending on the involvement of causal gene. The APP cleavage by β and γ-secretase generate Aβ peptide which is a crucial element of Aβ plagues. PSEN1 and PSEN2 are homologs parts of γ-secretase complex. Hence, genes related to Aβ biology and APP are associated with development of EOAD [61].

APP is transmembrane protein present at neuronal synapses which establish synapses and promote neuronal plasticity [62]. APP proteolysis by α and β-secretase releases soluble fractions sAPPα and sAPPβ, respectively. This process also produces the membrane embedded c-terminal fractions which are managed by the γ-secretase and release an extracellular Aβ peptide and intracellular AICD. This APP processing is majorly affected by the mutations in EOAD and leads to elevate the levels of cytotoxic Aβ42 peptides [59,63].

Presenilins are functional components of γ-secretase involved in the APP cleavage. PSEN1 is polytopic membrane protein located on the chromosome 14q24.2 [64]. All PSEN1 missense mutations promotes the cleavage of APP and responsible for the development of EOAD through the elevation of Aβ42 to Aβ40 ratio [65,66]. On chromosome 1q42.13, there is a gene called PSEN2 that resembles the PSEN1 in sequence homology and structural organization [66]. Like PSEN1, the missense mutations on PSEN2 causes detrimental functional effects. The familial AD (FAD) involving either PSEN1 or PSEN2 mutations are characterized based on disease onset age. Generally, PSEN1, PSEN2 and APP associated FAD occurs between the ages of 40–85, 35–55 and 45–65 years, respectively [64,66,67].

The early onset AD (EOAD) represents a dominantly inherited AD. However, late onset AD (LOAD) or sporadic AD is distinct etiologically from the EOAD. The LOAD shows the involvement of both environmental and genetic factors [66]. APOE gene is present at chromosome 19q13.2. An epsilon allele in apolipoprotein E gene (APOE ε4) is connected with early disease onset and elevated risk of AD in late onset and sporadic AD [59,68,69].

The several AD associated genes are represented as Table 1.1 along with synonyms, gene ID and chromosomal location [66,70–72].

Table 1.1

The synonyms, ID and chromosomal locations of presented genes are according to the National Library of Medicine, National center for Biotechnology Information (NCBI); January 2023, Gene Database (https://www.ncbi.nlm.nih.gov/gene).

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Chapter 2: Neuroinflammation in Alzheimer's disease

Mohit Agrawala, Manmohan Singhalb, Bhupendra Gopalbhai Prajapatic, Hema Chaudharya, Yash Jasoriaa, Bhavna Kumarb, Mandeep Kumar Arorab, and Jagannath Sahoob     aSchool of Medical & Allied Sciences, K.R. Mangalam University, Gurugram, Haryana, India     bFaculty of Pharmacy, DIT University, Dehradun, Uttrakhand, India     cShree S.K. Patel College of Pharmaceutical Education and Research, Ganpat University, Mehsana, Gujarat, India

Abstract

Alzheimer's disease (AD), a pathology first described by Alois Alzheimer in 1906, It is a neurodegenerative disorder that is the most common cause of dementia which is characterized by functional and neuronal loss in the brain. It has recently been suggested that mechanisms like chronic neuroinflammation may occur before amyloid-β and tau pathologies in late-onset Alzheimer's disease Neuro-pathological criteria are senile plaques that can potentially get between the neurons, resulting in the accumulation of an inflammatory reaction around deposits of amyloid, fibrillary protein, Aβ, the beta-amyloid precursor protein (APP) and neurofibrillary tangles. Irrespective of the source and mechanisms that lead to the generation of reactive oxygen species, mammalian cells have developed highly regulated inducible defense systems, whose cytoprotective functions are essential in terms of cell survival. Some experts have proposed that Inflammation clears in pathologically vulnerable regions of AD and several inflammatory factors influencing AD development, i.e., environmental and/or genetic factors have been described. Obesity and systemic inflammation may also interfere with immunological processes which promote disease progression. This study suggest that assess the association between neuroinflammation and a variety of clinical studies and treatment strategies for Alzheimer's disease and some natural compounds may also provide a new therapeutic line of approach to this brain neurodegenerative disorder.

Keywords

Alzheimer's; Amyloid precursor protein (APP); Neurodegenerative; Neuroinflammation; Systemic inflammation

1. Introduction

Alzheimer's disease (AD), the most common type of dementia, is defined as a progressive decline in a person's cognitive, behavioral, and social skills and impairs their ability to function independently. According to WHO, the disease is anticipated to afflict 152 million people by 2050, with an estimated 57 million individuals affected as of 2019 [1]. Despite the fact that the exact cause of AD is uncertain, two important players are frequently named in its progression: β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs). Pathology is caused by incorrect cleavage of the amyloid precursor protein (APP), which results in Aβ monomers that aggregate to form Aβ fibrils and plaques [2]. The second core disease, NFT, is caused by the hyperphosphorylation of tau, a microtubule-associated protein that maintains microtubules [3]. Due to the causative mutations discovered in the APP, the amyloid hypothesis has emerged as the leading theory in AD research. It is thought that endosomes or the cell surface are where the APP is processed posttranslationally. The synthesis of amyloid beta (Aβ) results from its processing by either β- then γ-secretase (amyloidogenic pathway) or then - α- then γ-secretase (nonamyloidogenic) (Fig. 2.1) [4]. These build up close to neurons and inhibit mitochondrial activity, which leads to aberrant synaptic functioning, and lower levels of neurotransmitters like acetylcholine. These plaques may also trigger an immunological response and inflammation, both of which have the potential to harm nearby neurons. Amyloid Angiopathy, which weakens blood vessel walls and raises the risk of bleeding, rupture, and blood loss, can also form around blood vessels in the brain.

The intracellular hyperphosphorylated tau protein aggregates known as a neurofibrillary tangle, which are also a hallmark of AD, are another significant aspect of the condition. Neurofibrillary tau tangles (NFTs) build up as a result of the microtubule-associated protein Tau aggregation (Fig. 2.2). Microtubule stability is thought to be aided by tau. PHFs—insoluble paired helical fragments—are produced as a result of hyperphosphorylated tau polymerization and go on to combine into NFTs. Neurons with tangles and dysfunctional microtubules are less able to communicate and may experience apoptosis, or programmed cell death.

2. History of neuroinflammation in AD

Oskar Fisher, a pioneer in AD research, felt that senile plaques are the consequence of a foreign material deposition that may produce an inflammatory reaction, resulting in an abnormal neuritic response of the surrounding neurons [5]. The overall perspective of neuroinflammation response in AD, which leads to neuronal loss, and the innate immune system, which originates the majority of the reaction, has been revolutionarily constructed for it [6]. Misfolded and aggregated proteins link to pattern recognition receptors on microglia and astrocytes, resulting in the production of A1 beta, TNF alpha, nitric oxide, and other inflammatory mediators, which triggers an innate immune response that increases the severity and duration of the ailment. A notable example of the reduction of long-term potentiation in the hippocampus is caused by these inflammatory mediators, which are also able to functionally affect neural network functioning. Numerous genes are anticipated to encode proteins that affect the inflammatory response and the glial clearance of misfolded proteins, and these genes are also associated with a higher risk of AD [7].

Fig. 2.1  Aβ precursor protein (APP) is hypothesized to undergo posttranslational modification within endosomes or on the cell surface. It involves either cleavage either β- then γ-secretase (amyloidogenic pathway) or then - α- then γ-secretase (nonamyloidogenic).

Fig. 2.2  Neurofibrillary tau tangles (NFTs) build up as a result of microtubule-associated protein tau (MAPT) aggregation.

3. The concept of neuroinflammation in AD

Neuroinflammation initially functions as a defensive mechanism for the brain in neurodegenerative illnesses like AD by eradicating or suppressing infections. A continuous inflammatory reaction is harmful and prevents them from regenerating. This inflammatory response aids in tissue healing and helps eliminate cellular waste. Focusing on the functions of microglia and astrocytes as well as their interactions, we research the involvement of inflammatory responses in neurodegenerative illnesses such as AD, PD, HD, and ALS. The CNS's inflammatory response is mostly mediated by microglia and astrocytes. Biomarkers are used to assess neuroinflammation as well [8].

Fig. 2.3  The involvement of neuroinflammation in amyloid toxicity in Alzheimer's disease. Reproduced from Ref. [12] with permission.

Microglia account for 10%–12% of all cells identified in the brain. As resident macrophage cells, they are involved in homeostasis and serve as the primary and most important kind of active immunological defense against pathogens in the CNS [9]. Depending on their level of activation, microglia in the CNS can be either proinflammatory or neuroprotective. In response to specific stimuli, microglia produce chemokines such as the CCL2 and proinflammatory cytokines such as TNF, and IL to recruit new cells and eliminate harmful microorganisms. Consistent neuroinflammation causes neurotoxicity, which eventually results in neurodegeneration [10].

Nevertheless, 20%–40% of all the cells in a mammalian brain are astrocytes. Astrocyte cells control trophic chemical secretion, blood-brain barrier (BBB) integrity maintenance, proper synaptic function, neuronal metabolism, and local blood supply [11]. Both proinflammatory and immunoregulatory reactions are mediated by astrocytes. However, the different A complexes interact with expressed pattern recognition receptors in astrocytes and microglia that trigger innate immunity. This process results in an immune response that is dysregulated and, in excess, contributes to neurodegeneration. During this process, proinflammatory cytokines, chemokines, and reactive oxygen species are produced.

There is currently no cure for Alzheimer's, and treatments that might block the disease's fundamental progression only temporarily relieve symptoms. In experimental animal models of AD, NSAIDs have been proven to decrease amyloid deposition and microglial activation [12] (Fig. 2.3).

4. Neuroinflammation: Causes and consequences of Alzheimer's disease

About 2 decades ago, several experts proposed that neuroinflammation is fundamentally related to the onset of AD [13]. Early studies revealed that the complement and innate immune systems are active in AD patients' brains. Histochemical investigations also show that microglia are always active in the vicinity of amyloid plaques, most likely to phagocytose amyloid deposits [14]. Furthermore, studies have shown that proinflammatory cytokines including IL1- and TNF-are present in increased concentrations in AD brains as well as in patient blood [15]. Since activated microglia are usually present around amyloid plaques, which are considered to be directly connected with disease etiology, as a result of AD pathology, it has been proposed that neuroinflammation enhances the negative effects brought on by amyloid plaques. Nevertheless, several recent research has called into question this interpretation, and fresh information raises the possibility that persistent neuroinflammation may potentially contribute to AD. As previously mentioned, systems biology research on AD brains suggests that neuroinflammation may be causative in the pathogenesis of late-onset AD [16]. It's interesting to note that recent research found compelling evidence that amyloid deposition can be caused by persistent inflammation. Injecting poly IC, which stimulates the TLR signaling pathway and causes proinflammatory reactions, generated systemic inflammation, which led to amyloid deposition in wild-type mice and aggravated amyloid pathology in a 3XTg animal model of AD, according to research by Krstic et al. We evaluated and measured the directed motile and phagocytic activity of microglia in AD mouse models using two-photon microscopy and acute brain slice samples. Additionally, by delivering the A-specific antibody Ab9 to Alzheimer's disease-affected rats, we investigated if this interventional treatment recovers AD-associated functional abnormalities in microglia by reducing Aβ plaque deposition. Our research using two independent mouse models of AD provides new information about the precise behavioral changes that occur during the illness and raises the possibility that plaque deposition and microglial function are tightly connected [17].

Studies on individuals without dementia have indicated a link between low-grade peripheral systemic inflammation and higher cognitive deterioration, including smaller hippocampus volumes. Furthermore, some studies—but not all—have linked a higher degree of systemic inflammation to an elevated risk of AD. However, despite the existence of a few preliminary studies, no prospective longitudinal research has examined the influence of acute or ongoing inflammation on the progression of the ailment in large populations of individuals with established AD. Systemic synthesis of C-reactive protein (CRP) from the liver and the proinflammatory cytokine TNF-α from macrophages define both acute and chronic systemic inflammation [18]. By triggering the central innate immune response, which includes microglial cells, TNF-α contributes to immune-to-brain communication. It has been suggested that a diagnostic test for AD patients may employ signature serum inflammatory chemicals. The blood-brain barrier can break down as a result of persistent peripheral immune system activity, exposing the brain parenchyma to serum proteins. Brain microglia get activated as a result, of secreting proinflammatory chemicals. An inflammatory environment can seriously impair synaptic function when present continuously, potentially inhibiting synaptic transmission. Additionally, through hormonal and neurological pathways, ongoing neuroinflammation can stimulate the peripheral immune system, resulting in a loop of low-grade inflammation [19,20]. Because proinflammatory cytokines inhibit synaptic transmission, persistent systemic and neuroinflammation can impair brain function and result in cognitive impairment.

5. BBB integrity and neuroinflammation

The blood-brain barrier (BBB), which is well-studied for its stringent regulation of the entrance of substances such as proteins and cells from the circulation into the CNS, provides a homeostatic environment for surrounding neurons and glial cells. Compared to peripheral organs, this characteristic is different. The BBB is created and maintained by endothelial cells, which work with pericytes, microglial cells, macrophages, and astrocytes to produce the appropriate tight junctions [21]. Amyloid-β and blood-brain barrier disruption may augment their impacts in AD, according to growing evidence. On the luminal surface of the cell lies a transporter called P-glycoprotein. Aβ is successfully moved from the brain to the bloodstream through BBB. Changes in the expression of the tight junction protein can be replicated and evaluated without interference in an externalized environment, such as an in vitro epithelial barrier. Determining the protein levels and cellular distribution of tight junction occludin and claudin-2 using western blot and immunofluorescence after treating barrier-forming MDCKI and II epithelial cells with Aβ42 [22]. Through endothelial toxicity and enhanced monocyte adhesion, Aβ buildup can cause BBB dysfunction. Inflammatory cytokines are one factor contributing to BBB malfunction. TNF, IL-1, and IL-17A, for instance, have all been implicated in the ability of the TJs and BBB permeability. In capillary cerebral amyloid angiopathy, the neuroinflammatory response contributes to altered TJ expression, loss of BBB integrity, and changes in the BBB transcriptome. In the study, we investigated behavioral alterations and brain inflammatory responses generated by peripheral injection of lipopolysaccharide (LPS) and change in brain inflammatory cytokine (IL-6) level, using an Alzheimer APP-transgenic animal [23]. In this animal model of AD, the data show that the BBB is more susceptible to inflammation.

In research, BBB changes have typically been seen as a result rather than a cause because structural integrity has generally received more attention than functioning. According to a new study, the BBB's integrity is more crucial than initially assumed and that pharmacological modulation of the BBB may be a promising therapeutic goal for the treatment of AD.

6. Role of cellular players

6.1. Microglial

Microglial cells are macrophages that reside in the CNS. These cells appear to remain till maturity despite the fact that they develop quickly from progenitors in the yolk sac of the embryo. Microglia are present in 10%–12% of the brain throughout its development. Their primary roles involve assisting host defense AD by influencing the local astrocytes and neurons.

Furthermore, it has been demonstrated that inflammatory circumstances promote the addition of circulating myeloid progenitors and their development into microglia [24].

Reactive oxygen species, interleukin-1, tumor necrosis factor, and other neurotoxic chemicals, such as nitric oxide, are persistently produced by activated microglia and are thought to be responsible for the growing degeneration of neurons [25]. It is now beyond question that activated microglia contribute to neuronal loss and cognitive impairments in AD.

In vitro studies conducted by Mancilla et al. have demonstrated that proinflammatory cytokines produced by astrocytes, including IL-1, IL-6, and nitric oxide, accelerate tau phosphorylation and the formation of neurofibrillary tangles. Similar to how reactive oxygen species, microglial activation, and the proinflammatory cytokine TNF-α may lead to the accumulation of aggregation-prone tau molecules in neurites. In a triple-transgenic AD model, activated microglia were far more prevalent than nontransgenic controls, and their activation was strongly correlated with the production of Aβ plaques and smaller Aβ deposits. According to Serrano-Pozo et al., CD33 activation in microglia encourages Aβ42 pathogenesis in AD. Additionally, they suggest that pharmacological suppression of CD33 activity could restore the ability of Aβ to degrade microglia in AD [26,27].

6.2. Astroglia

However, mammalian brains contain 20%–40% of astrocytes. According to an increasing number of studies, Aβ also triggers an inflammatory response that is mediated by glial cells and contributes to cognitive loss and neurodegeneration. Aβ also causes the production of proinflammatory and inflammatory chemicals from astrocytes that overlap and are comparable to those produced by microglia. Proinflammatory cytokines (including TNF-, IL-1, and IL-6) and prostaglandins are among the metabolic processes linked to astrocytosis. Nitric oxide (NO), reactive oxygen species, and these substances are also involved. All of these processes have the potential to be detrimental to the health and function of neurons. Additionally, in the AD brain and transgenic AD models, calcineurin, a protein phosphatase that controls inflammatory responses, is strongly expressed by a large number of activated astrocytes [28].

Carrero et al. examined the involvement of NF-κB as a signaling channel in the early phases of Aβ-toxicity and showed that reactive astrocytes produce COX-2 and cytokines like IL-1β and TNF-α [29].

According to the already known data, Aβ activates astrocytes, which secrete inflammatory compounds that harm synaptic and neuronal function in cell models of AD.

6.3. Blood-derived mononuclear cells

The exact mechanism by which blood-derived mononuclear cells penetrate the CNS, which includes innate immune responses of the brain, is unknown because human research is restricted to animal studies. In transgenic mice models of AD, there is a significant infiltration of peripheral mononuclear cells that are highly ramified and elongated microglia into the core of amyloid plaques [14]. The elimination of CD11b-positive cells in the APP/PS1 mice model of AD also clearly illustrated the critical function peripheral mononuclear phagocytes play in restricting the formation of Aβ plaques. These brain mononuclear phagocytes, which also contain microglia, express several chemokine receptors, such as CCR2 in AD. In this work, we present evidence that, in a transgenic mouse model of AD, CCR2 deletion accelerates the early course of the illness and greatly reduces microglial buildup (Tg2576) [30]. It should be noted that in this instance, two separate APP transgenic mice strains with CD11b-HSVTK animals were employed, and practically complete microglia ablation was achieved for up to 4 weeks after ganciclovir injection [31].

These studies deny the assumption that blood-derived monocytes play a significant role in clearing CNS Aβ deposits, but they do support the hypothesis that perivascular macrophages contribute in some manner.

7. Role of mediators and modulators in neuroinflammation

7.1. Cytokines

The main cells that create cytokines in AD are probably microglia and astrocytes. Cytokines are involved in both pro and antiinflammatory processes, unintentional neuronal injury, chemoattraction, and the microglia's response to Aβ deposits in terms of neuroinflammation [32].

It has been established that cytokines including IL-1, IL-6, TNF-α, and TGF-β are primarily responsible for mediating this inflammatory process [33].

7.2. Interleukin-1 (IL-1)

The production of IL-1 has increased in the Immunohistochemistry of microglia to be more specific, these IL-1-positive microglia are present in the vicinity of amyloid deposits and appear to be involved in plaque development. Numerous investigations demonstrating IL-β immunolabeling in astrocytes and hepatocytes support these conclusions. The amyloid aggregates' immediate surroundings in microglia mice with a transgenic form of APP that overexpress FAD mutations (Tg2576). On the other hand, evidence suggests amyloid-beta peptide-treated cultured astrocytes and microglia. However, both in vitro and in vivo research have linked IL-1 to the synthesis of the amyloid precursor protein. As a result, IL-β stimulates the transcription of APP in neurons and astrocytes. Furthermore, intracerebral injection of IL-1β led to an overexpression of APP in rat brains. These findings demonstrate that IL-1 is secreted by microglia and astrocytes in response to the buildup of Aβ peptide and that this action initiates a positive feedback loop that increases Aβ synthesis