INTRODUCTION:

ALZHEIMERS DISEASE:

One of the most significant challenges to medical science in this century is AD. It is anticipated that 40 million individuals would be affected globally, and that number will increase every 20 years until around 2050¹. The main cause of dementia, according to study, is a neurodegenerative condition that affects between 60% and 80% of cases. It manifests as problems with a gradual deterioration in mental capacities, including the communication skills, consciousness, and cognitive abilities needed for daily tasks².

The characteristic feature of [AD] is a gradually worsening neurological disease that results in amyloid-beta peptide buildup the medial temporal cortex and neocortical structures, the brain regions most damaged, producing neurotic plaques and neurofibrillary tangles³. Alzheimer's disease is characterized by two key neuropathological features: intracellular neurofibrillary tangles (NFT) and extracellular amyloid β (Aβ) production in the form of plaques. The initial histopathologic features of AD to be recognized were extracellular amyloid plaques and intracellular neurofibrillary tangles. Other recently identified histologic indicators are aneuploidy, synaptic degeneration, and loss of hippocampal neurons⁴.

ETIOLOGY AND PATHOPHYSIOLOGY OF ALZHEIMERS DISEASE:

There may be genetic and environmental risk factors that impact the development of AD. The primary risk factor for AD is age; at 65, the risk is around 3%, and by 85, it is more than 30%. Though it's unclear how often AD is in those under 65⁵. Additionally, research shows that Apolipoprotein ε4 gene allele increases the risk of AD with a delayed start⁶. AD is brought on by genetic mutations in the γ-secretase proteins Presenilin-1 (PS1) and Presenilin-2 (PS2), as well as the Amyloid Precursor Protein (APP)⁷.

APP buildup at presynaptic terminals, where it is transported by axons may cause Aβ deposition at synapses when elevated to comparatively greater levels ⁸, Because it damages neurons in AD, this Aβ is categorized as a neurotoxic material and is thought to be the primary contributing factor to dementia⁹. Apart from the above-mentioned components, depression, smoking, excessive alcohol use, obesity, diabetes mellitus, increased cholesterol, heart disease, cerebrovascular disease, and elevated cholesterol are other variables that may be risk factors for AD¹⁰.

PATHOPHYSIOLOGY OF ALZHEIMERS:

It is still unclear how AD pathogenesis and neuronal death occur. To shed light on the origins and workings of AD, several theories have been advanced. It's feasible that distinct risk factor combinations within various individuals might result in distinct ways for the illness to be triggered, eventually leading to a shared degenerative pathway¹¹. AD-related neuronal deterioration, which causes synaptic loss given the modest concentration of neurotransmitters in the brain is what causes these changes¹².

Mutations in three important genes that encode the proteins stenilin-1 (PS1), stenilin-2 (PS2), and amyloid precursor protein (APP) on chromosome 21 that are said to be the cause of the same¹³. These genes’ mutations result in hyperphosphorylation of amyloid protein, which forms senile Tau protein and extracellular space plaques, which generates intracellular neurofibrillary tangles¹⁴. It is becoming more and more clear that pathogenic Aβ oligomers and aberrantly increased tau hyperphosphorylation work together to cause the neuronal dysfunction and death of cells that underpin cognitive decline. Amyloid hypothesis suggests the tau disease is predominantly caused by neurotoxic Aβ; however, tau changes also seem to be caused by additional human APP proteolytic fragments, such as sAPP, N-APP, and AICD¹⁵.

2.1. AMYLOID HYPOTHESIS:

After it was found, the amyloid hypothesis was created that dementia is strongly correlated with aberrant β-sheet deposition in the central nervous system¹⁶, Currently, the disease’s two main contributing components are as tau tangles with beta amyloid plaques¹⁷.

Alpha- and gamma-secretase enzymes will break down the [APP]. Comprises three regions in healthy neurons; the cell membrane, the cell interior, and the cell exterior. It is during this digestive process that certain soluble polypeptides are created that can be recycled and eventually decompose. The scenario takes a wrong way when the gamma- and beta-secretases work together. An insoluble amyloid-beta peptide is the end product of this digestion process.

Amyloid-beta peptides clump together to form Beta amyloid plaques (AβP).

When AβP develops, it might lead to major issues within the cell between two healthy neurons, β1, AβP may find and interfere with their signalling procedure¹⁸. Additional reports state that AβP can initiate an inflammatory immune response that could harm nearby neurons¹⁹. Angiopathy is the term for when AβP deposits on the outside of blood vessels. Finally, angiopathy will result in bleeding or a vascular rupture²⁰.

GENETICS AND RISK FACTORS:

Eventually, it became clear that genetic factors were mostly accountable for Alzheimer's disease development. Apolipoprotein E, Amyloid Prototype Protein (APP), Presenilin-1 (PSEN-1), and Presenilin-2 (PSEN-2) are among the prevailing genes associated with AD. Furthermore, most cases of AD that start early (EOAD) patients follow an autosomal dominant pattern of inheritance. Genetic factors account for 70% of those cases of AD²¹.

AMYLOID PRECURSOR PROTIEN [APP]:

APP is a type 1 transmembrane protein that is produced by the APP geneβ on chromosome 21. Aβ and other proteins are released when α, β, and γ-secretase cleaves it. By reducing the release of Aβ, Aβ 40, and Aβ 42, the protective mutation A673T inhibits AD²². All changes concentrate on the site of secretase cleavage point. The km670/671NL mutation, for example, has been associated with an increase in cerebral and hippocampal amyloid plaques, but not NFTs in animal models. Mutations Atrophy of the cortex has been shown in A673V, D678H, D678N, E682K, and K687N, whereas atrophy of the hippocampus has been shown in E682K. Compared to the other mutations discussed, which demonstrate an unchanged intracellular Aβ, neuropathological studies demonstrated the presence of NFTs and Aβ, astrocyte and microglia activation, and neuronal death for the A673V mutation^23,24.

Further mutations affecting the γ-secretase cleavage site include T714I, V715A, V715M, V717I, V717L, L723P, K724N, and I716V. On the other hand, mutations affecting the α-secretase cleavage site include E693G, E693K, D694N, and A692G, which result in polymorphic aggregates that can compromise the integrity of the bilayer. Moreover, the deletion mutation E693 delta promotes the synthesis of synaptic lethal Aβ²⁵.

Presenilin 1 & Presenilin 2:

The PSEN 1 and PSEN 2 genes are located on chromosomes 14 and 1 represent the autosomal dominant type of EOAD. They are almost similar, with 67% of the same properties, while they differ at the hydrophilic region and the N-terminus. APP processing is carried out by the parts of the enzyme complex γ-secretase that are catalytic, are encoded by presenilin 10 (PSEN1) and 20 (PSEN2)²⁶. PSEN1 has been discovered to contain PSEN 2 gene mutations appear to be rare, as evidenced by the fact that the gene contains less than 40 mutations out of more than 200.Aβ 40 levels are decreased by mutations in the PSEN1 gene, which raises the Aβ 42/Aβ 40 ratio²⁷. Studies reveal that, akin to APP mutations, PSEN1 and PSEN2 mutations modify the synthesis of Aβ²⁸.

Apolipoprotein E (ApoE):

The production of myelin and healthy brain function depend on the glycoprotein ApoE protein serving as an endocytosis ligan for lipoprotein particles, such as cholesterol, by receptor-mediated means it is highly expressed by some microglia and astrocytes in the brain and liver. The coding sequence of the ApoE gene on chromosome 19 is altered by single-nucleotide polymorphisms (SNPs), resulting in the existence of three isoforms: ApoE2, ApoE3, and ApoE4. The ApoE4 allele is linked to a greater risk for EOAD and LOAD compared to the ApoEε2 and ApoEε3 alleles, which are linked to a reduced risk and a protective impact, respectively²⁹.

ApoEε4 is implicated in the generation of cerebral amyloid angiopathy (CAA), a characteristic linked to AD, and in the deposition of Aβ as a senile plaque³⁰. Additionally, it has been demonstrated that ApoEε4 is linked to brain vascular injury, which triggers the pathogenesis of AD³¹.

TAU HYPOTHESIS:

The amino acid residue next to proline, serine, and threonine are the three locations where the tau protein is phosphorylated. This is where it affixes itself to microtubules. It is predominantly at positions T231, S235, and S265 where the protein is hyperphosphorylated. Following this, protein is unable to bind to microtubules and create neurofibrillary tangles³². All biochemical communication inside and between cells is so hindered, and there is damage to the cell’s cytoskeleton. Microtubules packing structure is improved by tau proteins on their surface. Exon 10 encodes thirty-one or thirty-two amino acids, which are repeated three or four times semi-homologous. From the carboxy-terminal part of the microtubule, Tau then attaches itself to it³³Activated kinases phosphatize the tau protein, which then departs from the microtubule as phosphorylated tau. Then, when all of the phosphorylated tau proteins get together, a neurofibrillary tangle is created. Without tau proteins, the microtubule would deteriorate and eventually lose its capacity to carry messages.

NEUROINFLAMMATION:

The term "neuroinflammation" refers to the inflammatory response of the central nervous system (CNS) to chemicals that disrupt homeostasis. Numerous CNS cell types, including This reaction involves microglia and astrocytes³⁴. Activation of microglia is the primary component of neuroinflammation. When there are abnormalities in the homeostasis of the brain brought on by trauma, illness, stress, or pathology, microglia react quickly. When microglia are activated, a variety of inflammatory and cytotoxic chemicals that lead to neuroinflammation and neurodegeneration are produced.

Through the excessive production and release of pro-inflammatory cytokines and reactive oxygen and nitrogen species (RONS), age-related releases of damage-associated molecular patterns (DAMPs) such as extracellular ATP and circulating mitochondrial DNA from cell debris interact with the Nod-like receptor 3(NLRP3) to produce an oxidative and neuroinflammatory environment. Pro-inflammatory cytokines are also produced by senescence-associated secretory phenotype (SASP) factors and mitochondrial reactive oxygen species (mtROS) senescent cells, which cause neighbouring cells to likewise become senescent. This causes neuroinflammation and death of neurons³⁵.

DIAGNOSTIC BIOMARKERS FOR NEUROLOGICAL DISORDER:

AD biomarkers are needed to improve patient selection in clinical trials, even though for early treatment of high-risk individuals, long-term biomarkers are required, follow the course of the illness, and measure treatment response³⁶. Clinicians can benefit from both categories in recognizing, differentiating, and diagnosing AD symptoms. The quantities of tau and amyloid proteins in cerebrospinal fluid (CSF), the levels of these and more protein biomarkers in plasma, and amyloid positron emission tomography (PET) are a few pathophysiologic biomarkers associated with AD lesions³⁷. AD pathology is correlated with topographic indicators that show regional hypometabolism on tau PET, regional/local atrophy on structural magnetic resonance imaging, and fluorodeoxyglucose (FDG)-PET³⁸.

ALZHEIMERS DISEASE TREATMENT:

CURRENT TREATMENT AGENTS USED FOR ALZHEIMER’S DISEASE:

Alzheimer's disease therapy does not currently alter the illness's course or underlying pathology. However, attempts are undertaken to Utilize medicine and other therapy to improve AD patients' quality of life. Currently, memantine and cholinesterase inhibitors (donepezil, rivastigmine, tacrine, and galantamine) are the pharmacologic treatment obtainable for AD. An excitatory neurotransmitter associated with learning and memory; glutamate binds to NMDARs. Memantine is a dopamine agonist and non-competitive NMDA antagonist; it was the final medication to be licensed by the FDA. memantine has demonstrated a modest effectiveness and safety profile³⁹. Thus, in addition to treating AD symptoms, this medication has neuroprotective properties⁴⁰.

As such, three main MOAs have been the focus of anti-amyloid DMTs:

1. decrease in the synthesis of Aβ42 (γ-secretase potentiation, β-secretase inhibitors, γ-secretase inhibitors)

2. decrease in the load of Aβ-plaque (aggregation inhibitors, metal-interfering medications)

3. promotion of immunotherapy (passive or active) to remove Aβ⁴¹.

TARGETED PATHOLOGICAL PATHWAYS:

Based on current understanding, AD pathogenicity is initiated by the production of Aβ plaques. Neurons also die as a consequence of tau hyperphosphorylation-induced neurofibrillary tangles (NFTs). Therefore,

1. Blocking the secretases of α, β, and γ, the synthesis of Aβ peptides is reduced and plaque formation is prevented.

2. Tau phosphorylation will decrease with tau protein kinase inhibition, which will inhibit the development of NFTs.

3. using chemicals that can dissolve or remove NFTs and Aβ plaques⁴².

COMBINATION THERAPY:

COMBO treatment for AD, as opposed to CI monotherapy and no treatment, reduces the cognitive and practical deterioration in AD. Small-to-medium effect sizes were associated with these long-lasting benefits, and they improved with therapy⁴³. some examples for combinational drug therapy are:

Galantamine and memantine combined; memantine and nitro-glycerine combined; donepezil and clioquinol combined; combinations of propargylamine and VK-28; rasagiline and rivastigmine; assemblage of anti-tau agents;

Combination of Neurotrophic Agents; Combination of Antioxidative Factors; Combination of Anti-inflammatory Drugs; Cholinesterase inhibitor and memantine combination treatment for AD; Combination of Acetylcholinesterase inhibitor and memantine; Combination of Rivastigmine and Memantine; Combination of Donepezil and Memantine; The long-term total solution for AD patients, a donepezil and vitamin E combination appears to be advised⁴⁴.

FUTURE DIRECTION:

Antisense oligonucleotides (ASO) may be used in future targeted AD therapy attempts to change target expression. These tactics might be very helpful in the fight against tau disease^45,46. This same study also demonstrated that RNA interference therapy reduced oxidative stress indicators, which are commonly present in tissues impacted by tau disease⁴⁷, Even with aducanumab's possible success, the Aβ hypothesis-driven clinical failure has led to a growing interest in finding different biomolecular targets for AD therapy. It is possible to find new possible targets and investigate how certain therapies affect them using both proteomic and transcriptome techniques⁴⁸.

ALZHEIMER'S DISEASES AND STEM CELL THERAPY:

Stem cell treatment is a viable and successful restorative strategy for AD and a number of other neurodegenerative illnesses, based on the neurogenesis capacities of stem cells⁴⁹ the proposed technique replaces the neurons lost during the neurodegenerative stages of AD with stem cells. Neurons' extracellular environment is mostly regulated by glial cells and intercellular binding proteins. The strength of neuronal networks in the central nervous system is compromised and a significant loss of neurons occurs when astrocytes, oligodendrocytes, and microglia decrease⁵⁰. In situ regeneration or transplanting injured neurons slows the decline of mental capacity in AD patients and offers hope for the CNS to restore its dependability. The stem cells being produced by the human body are:

Neural Stem Cells (NSCs); Mesenchymal stem cells (MSCs); Embryonic stem cells (ECSs); Induced pluripotent stem cells (iPSCs); Hematopoietic stem cells (HSCs);

NEURAL STEM CELLS (NSCs):

The brain contains small numbers of multipotent stem cells called NSCs, which give rise to the neural cells that comprise the central nervous system (CNS)⁵¹. Functional neural cells can be differentiated and renewed by multipotent NSCs⁵². These cells are easily isolated from iPSCs and ESCs in newborn brain tissues from both postmortem and fatal sources⁵³. NSCs provide the ideal means of replacing lost neurons in the human brain⁵⁴. Possible therapy options using NSCs include the stimulation of neuronal cell development during particular morphogen interaction, which is then the patients’ overexpression of healthy cells⁵⁵. By increasing the quantity of Ach in CSF, according to a different study, cholinergic neuronal integrity was restored in AD rats treated with AF64A-cholonotoxin by transplanting human choline acetyltransferase (ChAT)-NSCs⁵⁶.

MESENCHYMAL STEM CELLS (MSCs):

MSCs represent an additional variety of multipotent stem cell lineages present in all human tissues. In the lungs, blood, adipose tissue, muscle, umbilical cord and bone marrow, they can develop into a wide variety of cells⁵⁷. Given their availability relative to NSCs, MSCs provide a viable approach for therapeutic stem cell therapies. The capacity to effectively migrate towards damaged brain regions and to cross the blood-brain barrier (BBB) are two characteristics that characterize MSCs. Moreover, MSCs may have therapeutic value for AD patients because of their less aggressive intravenous delivery method, which avoids immunogenicity and tumorigenicity and raises no ethical issues⁵⁸.

INDUCED PLURIPOTENT STEM CELLS (iPSCs):

Numerous cell types, including neurons and neutrospheres, are believed to be able to be differentiated from iPSCs⁵⁹. One way to investigate the inflammatory response in AD is by using glial cells produced from iPSCs⁶⁰Tissue-specific cells in mutant people resulting from FAD are effectively treated with APP using an iPSC paradigm⁶¹A246E-and N141I-mutant presenilin1 (PSEN 1) and PSEN 2 (N141I) neurons releases more Aβ42.⁶². APP processing and Aβ production when fAD-APP and PSEN1 mutations are present were simulated by numerous patient-derived iPSC neurons, implying that iPSCs are a useful model to investigate possible cellular dysfunction resulting from inherited fAD mutations⁶³.

NANOTECHNOLOGY-ASSISTED DRUG DELIVERY STRATEGIES FOR AD:

In order to overcome these challenges in drug delivery, recent advancements in nanotechnology have allowed us to employ nanoparticles. This is particularly useful in reducing side effects by using lower dosages and effortlessly navigating the blood-brain barrier to deliver the medication to the desired location. Some of the nanoparticles most often used are liposomes; polymeric nanoparticles; silicon nanoparticles; Lipid Nanoparticles; Magnetic Nanoparticles.

The nanoparticles to penetrate the BBB, their sizes must be between 1 and 100nm⁶⁴.

Their formulation renders them non-toxic, biodegradable, and tailored to a certain target⁶⁵. To optimize medication for individuals with AD, nanodevices may be delivered by nasal, cutaneous, or intravenous routes that cross the blood-brain barrier. As a result, these drugs will have improved pharmacologic qualities, increased bioavailability, and reduced side effects⁶⁶. While phagocytosis, pinocytosis, and receptor-mediated endocytosis are the three most common ways of transferring nanoparticles, The most effective technique is endocytosis mediated by receptors. Through processes of diffusion, erosion, or degradation, the integrated medication is transported to the intended location⁶⁷.

CONCLUSION:

For almost thirty years, research has been centred around the amyloid theory.

The lack of clinical success demonstrated by Aβ-targeting medicines thus far has led to scepticisms regarding this theory. The most often cited reason for these unfavourable findings is that the medications were investigated at the advanced phases of AD. Clinical effectiveness was not demonstrated in trials carried out in prodromal or even preclinical phases of AD. Clinical testing is ongoing for some Aβ immunotherapies, and predicted outcomes are being observed. It is evident that novel targets and treatment approaches must be sought after. Rather than being only a byproduct of the amyloid cascade, tau pathology appears to play a central role in the neurodegeneration associated with AD. As a result, in recent years, medicines that target tau have drawn more interest. Still in the early phases of clinical testing, the majority of anti-tau medications. Another more modern tactic put up by some writers is combination treatment. Combining these methods may be more beneficial than monotherapy because of the intricate pathophysiology of AD and the possible synergy between tau and Aβ. Furthermore, as it may offer a fresh tactic, it is imperative to comprehend the function of glial cells, specifically microglia and astrocytes, in the etiology of AD. In conclusion, further study is needed to get a greater understanding of the pathophysiology of AD and, as a result, identify novel targets and biomarkers that will make the development of a really disease-modifying strategy easier.

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Received on 05.05.2024 Modified on 28.05.2024

Res. J. Pharmacology and Pharmacodynamics.2024;16(3):226-232.

DOI: 10.52711/2321-5836.2024.00038