Pathological Progression of Alzheimer Disease
SUSHRUT -A Magazine of Pharmaceutical Sciences
Volume 1, Issue 1, August 2024, Pages 7-10
Pathological Progression of Alzheimer Disease
➧August, 2024 ➧ A MAGAZINE OF PHARMACEUTICAL SCIENCES ➧ 1Department of Pharmaceutical Sciences, Jharkhand Rai University, Ranchi, Jharkhand-834010, India ➧ Volume 1
Introduction
Alzheimer's disease (AD) is an incurable, debilitating sickness that causes cognitive and behavioural deterioration over a protracted period of time. Plaques form in the cerebral cortex and other regions involved in thought and decision-making in AD, including the hippocampus, a structure located deep within the brain that aids in memory encoding. Worldwide, there are more than 55 million dementia sufferers, 60% of whom reside in lowand middle-income nations. Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia among the elderly, marked by a gradual decline in cognitive functions such as memory, reasoning, and language skills1
Pathological progression
Because APP, PSEN1, PSEN2, and MAPT mutations are present in a very small number of cases with early-onset AD (EOAD), the dual amyloidogenic-tauopathic theory of AD has dominated the pathogenic universe of AD-related neurodegeneration (and divided the research community as well) for the past 50 years. However, this theory does not fully explain AD pathogenesis, and as a result, novel (or complementary) theories have been emerging during the past decades and in recent times [2][3].
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| Figure 1: Elements that contribute to the development of Alzheimer's disease. |
Genomic Defects
The "golden rule" of complex disorders, which states that the more genetic defects distributed in the human genome, the earlier the disease onset and the worse the response to conventional treatments; and the fewer pathogenic SNPs, the later the disease onset and the better the response to various pharmacological interventions, is fulfilled by AD, a complex polygenic/multifactorial disorder in which hundreds of polymorphic variants of risk may be involved.
Through the creation, destruction, or modification of microRNA (miRNA) binding sites, genetic variation linked to various disorders impedes the regulation of microRNAmediated processes. In the adult human brain, miRNA-target variability is a common occurrence that may affect gene expression under both normal and pathological circumstances. AD-related SNPs alter susceptibility to AD by interfering with the control of miRNA genes. Target SNPs found in seven genes linked to the prognosis for AD are among the significant interactions with the miRNAs miR-214, -23a & -23b, -486-3p, -30e, -143, - 128, -27a & -27b, -324-5p, and -422a. One factor contributing to the aberrant gene expression in AD is the dysregulated miRNA network.
Epigenetic Phenomena
The pathophysiology of complex illnesses, gene-gene and gene-environment interactions, and development and aging has all been shown to be significantly mediated by epigenetic factors. AD pathogenesis may be influenced by major epigenetic pathways, including noncoding RNA regulation, histone modifications and chromatin remodeling, and DNA methylation.
Cerebrovascular Dysfunction
Vascular and metabolic dysfunctions play a crucial role in Alzheimer's disease (AD) pathology, appearing early in the disease's progression. Cerebrovascular disease is more commonly observed in AD than in other neurodegenerative disorders, lowering the threshold for dementia. Early-stage indicators, such as global brain hypoperfusion, oxygen hypometabolism, and neurovascular decoupling, suggest early cerebral hemodynamic changes. Contributing factors include oxidative stress, amyloid-beta (Aβ) accumulation, genetic factors like the Ninjurin2 gene, and cardiovascular risks. Endothelial dysfunction and blood-brain barrier (BBB) breakdown lead to neuroinflammation, oxidative stress, and mitochondrial dysfunction, further exacerbating AD pathology. Chronic brain hypoperfusion can induce premature neuronal death. APOE-4 carriers show deficient brain hemodynamics compared to other variants. Cerebral amyloid angiopathy (CAA) causes intra-cerebral hemorrhages and contributes to AD progression through amyloid plaque deposition in blood vessels. Reduced clearance of Aβ due to decreased P-glycoprotein expression and other transporters worsens Aβ accumulation. Additionally, AD patients, especially those using atypical antipsychotic drugs, show increased risk of transitory ischemic attacks (TIA), while vascular dementia (VD) patients have a higher risk of ischemic stroke.
Phenotypic Expression of Amyloid Deposits and Neurofibrillary Tangles (NFTs)
The external and intracellular expressions of the AD neuropathological phenotype are βAmyloid deposits in senile and neuritic plaques and hyperphosphorylated tau proteins in NFTs, respectively. Additionally, there is selective neuronal loss in neocortical and hippocampal regions. The main (postmortem) diagnostic criterion for AD is the presence of an Aβ plaque in the brain. Aβ, a 39–43 amino acid peptide produced by the proteolytic cleavage of APP by β- and γ-secretases, is the primary constituent of senile plaques. Aβ is neurotoxic, and its aggregation state contributes to its neurotoxicity.
Neuronal Apoptosis
A pathognomonic finding in AD is neuronal loss, which is the last common pathway among several pathogenic processes leading to neurodegeneration in dementia. As far as structural brain biomarkers go, atrophy of the medial temporal lobe-particularly of the hippocampus and Para hippocampal gyrus is thought to be the most predictive. In contrast to the other parietal lobe regions, the medial and posterior regions appear to be more affected.
Neurotransmitter Deficits
A variety of neurotransmitter imbalances, including those caused by glutamate, acetylcholine, noradrenaline, dopamine, serotonin, and certain neuropeptides, have been suggested as the neurobiological cause of AD behavioral symptoms. The neurotransmission imbalance in AD is caused by altered neurotransmitter reuptake by vesicular glutamate transporters (VGLUTs), excitatory amino acid transporters (EAATs), the vesicular acetylcholine transporter (VAChT), the serotonin reuptake transporter (SERT), or the dopamine reuptake transporter (DAT). AD is associated with decreased levels of VGLUTs, EAAT1-3, VAChT, and SERT protein and mRNA4.
Oxidative Stress
Oxidative damage is a key pathogenic mechanism in neurodegeneration, particularly in Alzheimer's disease (AD), where it is more pronounced than in age-matched controls. Antioxidant capacity increases with disease severity, correlating with the Braak tangle stage and the amount of insoluble amyloid-beta (Aβ). Aβ accumulation in the mitochondria of AD patients and transgenic mouse models leads to free radical generation and neuronal stress. The mitochondrial enzyme presequence protease (PreP), which degrades Aβ, shows reduced activity in AD brains and transgenic mouse models, potentially due to increased reactive oxygen species (ROS) production. This reduction in PreP activity may contribute to Aβ accumulation, mitochondrial toxicity, and neuronal death. In APP/PS1 mice, age dependent increases in oxidative stress markers, loss of lipid asymmetry, and Aβ production are observed. Proteomic analysis of specific mouse models reveals age-dependent brain protein carbonylation targets, further highlighting the role of oxidative stress in AD pathology.
Cholesterol and Lipid Metabolism Dysfunction
Cholesterol is closely linked to the formation of amyloid plaques, a key feature in Alzheimer's disease (AD) pathology. Variants of the APOE gene, which influence cholesterol metabolism, play a significant role in the risk and progression of AD. Cholesterol has a protective effect against amyloid-beta (Aβ)-induced neuronal membrane disruption and inhibits β-sheet formation of Aβ on lipid bilayers. Genome-wide association studies have identified a significant association between pathways related to cholesterol metabolism and immune response in late-onset Alzheimer's disease (LOAD). Disturbances in intracellular lipid metabolism are observed in both cardiovascular and neurodegenerative diseases, influenced by genetic and lifestyle factors. Neural membranes contain various glycerophospholipids (GPs), which are crucial for membrane structure, fluidity, and ion permeability. GP degradation by phospholipase A2 releases important polyunsaturated fatty acids (PUFAs) like arachidonic acid and docosahexaenoic acid. The oxidation of these PUFAs, both enzymatically and nonenzymatically, produces lipid mediators associated with neuronal pathways involved in AD neurobiology.
Neuroinflammation and Immunopathology
Genes related to immune regulation and inflammation, along with abnormal cytokine levels, are linked to Alzheimer's disease (AD). Inflammatory processes are a key aspect of AD pathology. Microglia, immune cells in the brain, is involved in the response to amyloid-beta (Aβ) deposits, but often fails to clear them effectively. Oligomeric Aβ is more toxic than its fibrillar form, although fibrillar Aβ can increase microglial activity. The TNF-α signaling pathway is crucial in AD-related inflammation, with altered levels of TNF-α observed in patients. The miR-181 family, especially in astrocytes, influences the inflammatory response; its overexpression can lead to increased cell death and altered cytokine production. The progression from mild cognitive impairment (MCI) to AD is associated with increased inflammatory activity, particularly involving the TNF-α signaling system [5].
Neurotoxic Factors
Various toxic agents, including metals like aluminum, copper, zinc, and iron, as well as biotoxins and pesticides, are believed to contribute to neurodegeneration. Dysregulated homeostasis of transition metals is implicated in Alzheimer's disease (AD) pathogenesis. The genotoxic metabolite methylazoxymethanol (MAM), derived from the cycad azoxyglucoside cycasin, causes genetic alterations across various organisms, though adult nerve cells were previously thought to be unaffected. However, research demonstrated that a single dose of MAM acetate in adult C57BL6 wild-type mice leads to DNA damage, specifically O6- methyldeoxyguanosine (O6-mG) lesions. This damage was exacerbated in mice lacking the DNA repair enzyme MGMT, resulting in increased O6-mG DNA damage. The DNA damage was associated with altered expression of genes involved in cell-signaling pathways linked to cancer, neurodegenerative diseases, and neurodevelopmental disorders [6].
Conclusion
The pathological progression of Alzheimer's disease involves the gradual accumulation of amyloid-beta plaques and tau tangles in the brain, leading to neuronal loss, synaptic dysfunction, and cognitive decline. This process typically results in memory impairment, personality changes, and loss of daily functioning, ultimately culminating in severe dementia. Supportive therapy, lifestyle modifications, and medication can all be used to manage Alzheimer's disease. Drugs like NMDA receptor antagonists (like memantine) and cholinesterase inhibitors (like donepezil, rivastigmine) can help reduce symptoms and decrease the condition's progression. A balanced diet, frequent exercise, and cognitive activities are examples of lifestyle modifications that may promote brain health. Non-drug methods of treating behavioral and psychological disorders include establishing regular routines and a peaceful atmosphere. Comprehensive care also includes education about the condition and support for caregivers. These techniques can enhance quality of life even when there is no cure.
References and Biblography
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