ALZHEIMER’S DISEASE: PATHOLOGICAL HALLMARKS OF ALZHEIMER’S DISEASE

ALZHEIMER’S DISEASE: PATHOLOGICAL HALLMARKS OF ALZHEIMER’S DISEASE

Mayank Sharma, Nandini Sharma and Aayush Sharma *

Department of Pharmacology, Accurate College of Pharmacy, Greater Noida, Uttar Pradesh, India.

ABSTRACT: Dementia is a collection of symptoms, including memory loss and cognitive impairment, that cause neuronal disruption and lead to certain mental illnesses. The most common cause of dementia is Alzheimer's disease (AD). Potential causes of illness extension include tau aggregation, amyloid beta build-up outside of neurons, and the formation of neurofibrillary tangles (NFTs) inside neurons. At one point in time, Alzheimer's disease was the most common illness worldwide. The majority of research indicates that ROS (Reactive Oxygen Species) play a significant role in neurodegeneration and, eventually, Alzheimer's disease. Amyloid-peptide increases in Alzheimer's disease led to an increase in ROS production, which kills neurons. A transcription factor called Farnesoid X Receptor (FXR) regulates inflammation, oxidative stress (OS), and the brain's metabolism of fats and carbohydrates. Nuclear erythroid 2 related factor 2 (Nrf2) is a transcription factor that regulates the production of many antioxidant genes and is an essential regulator of neural defence against OS. According to certain studies, Nrf2 activation can regulate the expression and activity of FXR in the liver, suggesting that these two transcription factors work in concert. Even while the exact relationship between FXR and Nrf2 in the brain is not entirely understood, it is likely that comparable interactions occur in this case. Activating the FXR and Nrf2 pathways may, in general, decrease oxidative stress and inflammation in the brain, making them appealing therapeutic targets for neurological disorders associated with inflammation and OS.

Keywords: Alzheimer disease, Oxidative stress, FXR, Nrf2

INTRODUCTION: The major prevalent aspect of dementia is called Alzheimer's disease (AD), which can be usually characterized as a slowly progressing neurodegenerative condition and was named after the German psychiatrist Alois Alzheimer ¹.

It is characterized by the development of intracellular neurofibrillary tangles made primarily of hyperphosphorylated tau and extracellular plaques made primarily of amyloid (A), as well as an increasing neuronal loss, especially in the cerebral cortex and hippocampus, which impairs cognitive function, and their etiology is currently unclear. In fact, after much research, it is still unclear how Aβ accumulation and NFT production and deposition work, and there is no cure for this condition. Due to this, a number of signaling pathways associated with specific pathophysiological processes have been researched and assessed as potential targets for cutting-edge use of therapeutic approaches in treatment of AD in recent years. Dementia prevalent in South Asia was 1.9% in 2005; it is anticipated to rise to 3.6 million by 2020 and 7.5 million by 2040 ².

A rising proportion of people in India are getting older as a result of longer lifespan and lower fertility rates. Those older than 60 years old are anticipated to make up 19.1% of the population by 2050³. On basis of mild, moderate, and severe signs and symptoms are given in this ⁴ Table 1.

TABLE 1: SIGN AND SYMPTOMS OF AD

The severity of cognitive impairment and the histopathological changes are the key criteria used to classify AD clinically. Typically, four steps are mentioned ^{5, 6}.

Preclinical: As there aren't any obvious symptoms during this stage, it's frequently disregarded. Mild cognitive impairment is the typical classification. The hippocampus and entorhinal cortex are the first brain compartment to experience pathological alterations during this phase (later).

This stage's subjects exhibit modest impaired memory with comparatively sparse long-term memories from a symptomatologic perspective. There is no obvious impediment to their usual tasks.

Mild Alzheimer's disease: Behavioral abnormalities begin to appear in mild Alzheimer's disease at this stage. At this stage, the cerebral cortex begins to experience pathological changes. From a symptomatologic perspective, there is memory loss along with loss of the ability to retain newfound knowledge, forget about things and meetings, followed by a decline in problem-solving, decision-making, and executive functioning. Together with these symptoms, patients exhibit personality alterations and changes in mood, and a lack of spontaneity.

Moderate Alzheimer's disease: The symptoms worsen throughout this stage. Other areas responsible for language, thinking, and sensory analysis are affected by the pathological injury (cerebral cortex). Aside from a worsening of the symptoms from the earlier stages, behavioural issues and a propensity for social withdrawal start to show up. Language dysfunction and a decline in visual-spatial abilities follow. It should be noted that subjects struggle to identify their own loved ones at this time.

Severe Alzheimer's disease: that is severe: During this stage, patients entirely lose their independence in daily tasks. It is thought that all parts of the cortex are affected at this point by the pathological deterioration. When the affected person's cognitive abilities are at their lowest point, other systemic symptoms such as olfactory and autonomic dysfunction, sleeping problem, and extra pyramidal motor symptoms such as parkinson's disease symptoms and akathisia begin to appear.

NOTE- Several staging systems, like the one Braak & Braak introduced in 1996, were created for AD. This concept divides the course of AD into six stages based on topographical staging of neurofibrillary tangles. The Reagan Institute and National Institute on Aging's neuropathological criteria for the diagnosis of AD include this Braak’s stage ⁶.

FIG. 1: PATHOPHYSIOLOGY OF AD

Pathophysiology of Alzheimer Disease: The accumulation of improperly folded Amyloid β and phosphorylated tau-proteins patients' brainsis causally linked to degeneration of neurons, according to a considerable body of evidence from the previous 30 years of study on Alzheimer disease ⁹. The extracellular plaque deposits of the Aβ and neurofibrillary tangles of the microtubule binding phosphorylated protein tau are two characteristic pathologies essential for an Alzheimer disease (AD) diagnosis Fig. 1 ⁸.

Amyloid Beta Formation: Amyloid plaques, Senile amyloid plaques, or "miliary foci" are extracellular accumulations of the Aβ-40 &42peptides brought on by irregular sequencing of the amyloid precursor protein (APP) by the β & ϒ- secretases and a disequilibrium in the pathways for production and clearance, as stated by Alzheimer disease Fig. 2 ¹⁰. In healthy neurons, α & β-secretases break down APP, which has three domains: inside of the neuronal cell, in the neuronal cell membrane, and on the outside of the neuronal cell. During digestion, certain soluble polypeptides are created that can subsequently be disassembled and recycled inside the cell.

But, when β & ϒ-secretases work together, things go wrong. During this digestion process, the amyloid-beta peptide, an insoluble peptide, is formed (Aβ) ¹¹. During this digestion process, the amyloid-beta peptide, an insoluble peptide, is formed (A-beta). The amyloid beta plaques, may result from the aggregation of amyloid-beta peptides, are detrimental to the health of the cell ¹².

FIG. 2: AMYLOID BETA FORMATION

Neocortical early deposits can be detected (phase 1). A plaque then develops in limbic areas such the amygdala, cingulated gyrus, subiculum, and entorhinal cortex (phase 2). Aβ deposits in subcortical regions, such as the hypothalamus and basal neurons, indicate further development (phase 3). Moreover, plaques are visible in the cerebellar cortex in cases that are at the latter stages of the disease, affects the midbrain, pons, and medulla oblongata in the brainstem (phase 4), and in advanced cases, the cerebellar cortex as well (phase 5). Phase 1 and 2 were primarily seen in asymptomatic people, but phases 4 and 5 were connected to the existence of dementia ¹³. Research findings of familial Alzheimer disease cases with APP, PSEN1, or PSEN2 alterations provide the most conclusive evidence for Aβ accumulation. Being the precursor to Aβ peptides, APP influences the breakdown and accumulation of Aβ peptides. PSEN1 and PSEN2 are catalytic subunits of secretases that cleave APP. PSEN mutations produce low effective APP processing and production of Aβ peptides that are longer and more hydrophobic, contrary to what was previously understood ⁹.

TAU Pathology: The brain neurons axons have highest levels of tau protein expression, although it is also present in oligodendrocytes, non-neural tissues, and the soma to dendritic portion of neurons ¹⁴.

FIG. 3: TAU PHOSPHORYLATION (NORMAL AND DISEASE CONDITION)

The microtubule-attaching protein by assisting in the maintenance of stable axonal microtubules (MTs) in the brain, tau regulates axon transportation and development. Post-translational modifications (PTMs), primarily phosphorylation, govern Tau's binding to MTs as well as a number of other, less well-known roles ¹⁵. Phosphorylation is one posttranslational change that can result in neurotoxicity and aggregate formation ¹⁶. There are 85 potential sites of the phosphorylation of serine (S), threonine (T), and tyrosine (Y) in the phosphorylated protein tau. tau's proline-rich domain, which is on each side of the microtubule-binding domain, contains a large number of the phosphorylated tau residues ¹⁷. Neurons become malnourished as a result of hyperphosphorylation of particular amino acids in tau proteins, which leads to cell death in AD due to abnormalities in the cytoskeleton and transport system. The development of AD and other tauopathies, as well as intracellular neurofibrillary changes, are thus greatly influenced by hyperphosphorylated tau ¹⁸.

Tau goes through a number of post-translational alterations prior to the formation of tangles, which differ from the typical tau found in healthy brains. These modifications include hyperphosphorylation, acetylation, N-glycosylation, and truncation. Tau post-translational alterations promote tau misfolding and inhibit MT- tau from binding ¹⁹.

Microtubules function similarly to railroad rails in that they transmit nutrients and other chemicals. Tau-proteins serve as "ties" that hold the microtubule structure together. Tau proteins become knotted in Alzheimer disease, causing the microtubule structure to become unstable. Cell death occurs when axonal transport is disrupted Fig. 3.

Oxidative Stress: The mitochondrial process of oxidative Phosphorylation is a main source of generation of adenosine triphosphate (ATP). Free radicals are often referred to as reactive nitrogen species (RNS), ROS, and radicals with centres on carbon and Sulphur are produced ²⁰. Thus, the significance of OS in the both condition, acute and chronic brain stroke, traumatic brain damage, and neurodegenerative illnesses pathologies ²¹.

FIG. 4: ELECTRON TRANSPORT CHAIN AND ROS FORMATION

The free radical production is inextricably linked to metabolism and other enzymatic processes. Mitochondria (intracellular) and inflammation (extracellular) are the main producers of free radicals. These reactive compounds can damage DNA, proteins, and lipids when anti-oxidative processes are out of balance, leading to cell cytotoxicity and tissue injury. These mechanisms are tightly controlled during physiological circumstances ²².

According to current theories, OS is characterized by an imbalance in the formation of ROS, has a significant impact on age-related neurodegeneration & cognitive decline and anti-oxidative defence ²³. High amounts of oxidized proteins, advanced glycation products, lipid peroxidation, and the emergence of toxic chemical compounds, such as peroxides, alcohols, aldehydes, free carbonyles, ketones, and cholestenone, and also oxidative alteration in nuclear and mitochondrial DNA in neurons are all signs of increases in level of OS in AD Fig. 4 ²⁴.

Because the phospholipids in the CNS neuronal membrane are made up mostly of polyunsaturated fatty acids, this organ is extremely susceptible to damage from free radicals. These multiple binds allow for enhanced lipid peroxidation and hydrogen ion elimination, which is the most observable sign of degenerative change in AD ²⁵.

Mitochondrial dysfunction & OS are connected to each other in AD. ROS will be generated as a result during mitochondrial metabolism since neurons have a high energy need for their numerous metabolic activities. As a result, mitochondrial dysfunction may cause a rise in ROS production and consequent neuronal injury ²⁶.

Free radicals targeting phospholipid poly-unsaturated fatty acids in the phospholipid bilayer can induce oxidative stress, which can occur in peroxidation of lipid and the production of critical end products ²⁷.

The inner mitochondrial membrane holds the mitochondrial respiratory chain. It is made up of 5 complexes that’s are - I, II, III, IV, and V Table 2 ²⁸, which, as a part of an integrated system made up of five protein complexes, catalyse the conversion of adenosine diphosphate to adenosine triphosphate ²⁹.

TABLE 2: MITOCHONDRIAL COMPLEXES

When neuronal loss and other AD disorders cause inflammation, it initially acts as an immediate neuroprotective response; but, if the immune response continues, it becomes damaging and worsens the condition. The balance between anti & pro-inflammatory signaling is disturbed by activated microglia, which then release a number of damaging substances such cytokines (interleukins (IL) and tumour necrosis factors (TNF- α) & ROS ³⁰. Persistent neuroinflammation is thought to worsen amyloid and tau disorders. Cytokines, specifically IL-6, are thought t promote tau hyperphosphorylation by activating protein kinases. Moreover, IL-1 increases acetylcholinesterase (Ach E) expression and activity, resulting in in-vivo cholinergic dysfunction studies and cholinergic neuron death ³¹.

FXR (Farnesoid X Receptor) PATHWAY: The liver, colon, and kidney all have high levels of the FXR, a nuclear hormone receptor super family member that functions as ligand-activated transcription factors. But little is understood about the function of the FXR in the brain ³², that controls the transcription of several genes, along with the phosphorylation of nuclear factor kappa B (NF-kB) & AMP-activated protein kinase alpha (AMPKα) ³³. In the resting state, the combination of Kelch like ECH-associated protein 1 (Keap1) (master transcription factor) and Nrf2 sequesters the protein in the cytoplasm ^{34, 35}. Nrf2 enters the nucleus by altering Keap1's conformation. Controls a number of anti-oxidative genes by forms a complex to the anti-oxidative response elements (ARE) in a heterodimer with the tiny Maf protein, along with hemeoxygenase - 1, xenobiotic - metabolizing enzyme to protect neuronal cells against OS ^{36, 37}.

CONCLUSION: Two important transcription factors that are expressed in the CNS are Nrf2 and FXR. Specifically, the liver, gut, and kidney produce FXR, but recent studies have also shown its expression in the brain. FXR activation has been shown to regulate lipid& glucose metabolism, inflammation, and associated OS in the brain.

FIG. 5: POSSIBLE FXR PATHWAY

The cellular defence against oxidative stress is crucially regulated by the Nrf2 transcription factor, however, which controls the various antioxidant genes expression in body. Nrf2 activation also has been shown to provide neuroprotection by reducing ROS induced damage in the CNS. Studies have suggested a potential interaction between FXR and Nrf2 in the brain. There may be a connection between the FXR and Nrf2-mediated antioxidant response as evidenced by the finding that activation of the FXR regulates the expression of Nrf2 and its associated genes expression in the liver.

Additionally, studies have shown that activation of Nrf2can regulate FXR expression and activity in the liver, suggesting a reciprocal relationship between these two transcription factors. Although the precise link between

Nrf2 and FXR in the brain is unknown, it is probable that comparable interactions take place in this context Fig. 5. Overall, the activation of FXR and Nrf2 pathways may have synergistic effects on reducing oxidative stress and inflammation in the brain, making them potential therapeutic targets for neurological diseases like AD (oxidative stress induced by ROS and inflammation).

ACKNOWLEDGMENTS: The authors would like to extend their appreciation to their co-authors and co-workers listed in the cited references.

CONFLICT OF INTEREST: The authors have no conflicts of interest regarding this investigation.

REFERENCES:

1. Breijyeh Z and Karaman R: Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules 2020; 25(24): 5789.
2. Mincic AM, Antal M, Filip L and Miere D: Modulation of gut microbiome in the treatment of neurodegenerative diseases: A systematic review. Clinical Nutrition 2024.
3. Ravindranath V and Sundarakumar JS: Changing demography and the challenge of dementia in India. Nature Reviews Neurology 2021; 17(12): 747-758.
4. Duggal P and Mehan S: Neuroprotective approach of anti-cancer microtubule stabilizers against tauopathy associated dementia: Current status of clinical and preclinical findings. Journal of Alzheimer's Disease Reports 2019; 3(1): 179-218.
5. Roy RG, Mandal PK and Maroon JC: Oxidative stress occurs prior to amyloid Aβ plaque formation and tau phosphorylation in Alzheimer’s disease: Role of glutathione and metal ions. ACS Chemical Neuroscience 2023; 14(17): 2944-2954.
6. Abbas K, Mustafa M, Alam M, Habib S, Ahmad W, Adnan M, Hassan MI and Usmani N: Multi-target approach to Alzheimer’s disease prevention and treatment: antioxidant, anti-inflammatory, and amyloid-modulating mechanisms. Neurogenetics 2025; 26(1): 1-20.
7. Lim D, Matute C, Cavaliere F and Verkhratsky A: Neuroglia in neurodegeneration: Alzheimer, Parkinson, and Huntington disease. Handbook of Clinical Neurology 2025; 210: 9-44.
8. Singh D: Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer’s disease. Journal of Neuroinflammation 2022; 19(1): 206.
9. Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J and van der Flier, WM: Alzheimer's disease. The Lancet 2021; 397(10284): 1577-1590.
10. Raulin AC, Doss SV, Trottier ZA, Ikezu TC, Bu G and Liu CC: ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Molecular Neurodegeneration 2022; 17(1): 72.
11. Ashrafian H, Zadeh EH and Khan RH: Review on Alzheimer's disease: inhibition of amyloid beta and tau tangle formation. International Journal of Biological Macromolecules 2021; 167: 382-394.
12. Thakral S, Yadav A, Singh V, Kumar M, Kumar P, Narang R, Sudhakar K, Verma A, Khalilullah H, Jaremko M and Emwas AH:. Alzheimer's disease: Molecular aspects and treatment opportunities using herbal drugs. Ageing Research Reviews 2023; 88: 101960.
13. Karran E and De Strooper B: The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nature reviews Drug Discovery 2022; 21(4): 306-318.
14. Rehman MU, Sehar N, Dar NJ, Khan A, Arafah A, Rashid S, Rashid SM and Ganaie MA: Mitochondrial dysfunctions, oxidative stress and neuroinflammation as therapeutic targets for neurodegenerative diseases: An update on current advances and impediments. Neuroscience & Biobehavioral Reviews 2023; 144:.104961.
15. Wegmann S, Biernat J and Mandelkow E: A current view on Tau protein phosphorylation in Alzheimer's disease. Current opinion in neurobiology 2021; 69: 131-138.
16. Zhang W, Young JI, Gomez L, Schmidt MA, Lukacsovich D, Varma A, Chen XS, Martin ER and Wang L: Distinct CSF biomarker-associated DNA methylation in Alzheimer’s disease and cognitively normal subjects. Alzheimer's Research & Therapy 2023; 15(1): 78.
17. Congdon EE, Ji C, Tetlow AM, Jiang Y and Sigurdsson EM: Tau-targeting therapies for Alzheimer disease: current status and future directions. Nature Reviews Neurology 2023; 19(12): 715-736.
18. Cheong SL, Tiew JK, Fong YH, Leong HW, Chan YM, Chan ZL and Kong EWJ: Current pharmacotherapy and multi-target approaches for Alzheimer’s disease. Pharmaceuticals 2022; 15(12): 1560.
19. Ossenkoppele R, van der Kant R and Hansson O: Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials. The Lancet Neurology 2022; 21(8): 726-734.
20. Salim S: Oxidative stress and the central nervous system. The Journal of Pharmacology and Experimental Therapeutics 2017; 360(1): 201-205.
21. Jelinek M, Jurajda M and Duris K: Oxidative stress in the brain: basic concepts and treatment strategies in stroke. Antioxidants 2021; 10(12): 1886.
22. Kamal FZ, Lefter R, Jaber H, Balmus IM, Ciobica A and Iordache AC: The role of potential oxidative biomarkers in the prognosis of acute ischemic stroke and the exploration of antioxidants as possible preventive and treatment options. International Journal of Molecular Sciences 2023; 24(7): 6389.
23. Jena AB, Samal RR, Bhol NK and Duttaroy AK: Cellular Red-Ox system in health and disease: The latest update. Biomedicine & Pharmacotherapy 2023; 162: 114606.
24. Gadhave K, Kumar D, Uversky VN and Giri R: A multitude of signaling pathways associated with Alzheimer's disease and their roles in AD pathogenesis and therapy. Medicinal Research Reviews 2021; 41(5): 2689-2745.
25. Huang WJ, Zhang XIA and Chen WW: Role of oxidative stress in Alzheimer's disease. Biomedical Reports 2016; 4(5): 519-522.
26. Zhu HY, Hong FF and Yang SL: The roles of nitric oxide synthase/nitric oxide pathway in the pathology of vascular dementia and related therapeutic approaches. International Journal of Molecular Sciences 2021; 22(9): 4540.
27. Singh P, Barman B and Thakur MK: Oxidative stress-mediated memory impairment during aging and its therapeutic intervention by natural bioactive compounds. Frontiers in Aging Neuroscience 2022; 14: 944697.
28. Basu U, Bostwick AM, Das K, Dittenhafer-Reed KE and Patel SS: Structure, mechanism, and regulation of mitochondrial DNA transcription initiation. Journal of Biological Chemistry 2020; 295(52): 18406-18425.
29. Vercellino I and Sazanov LA: The assembly, regulation and function of the mitochondrial respiratory chain. Nature reviews Molecular Cell Biology 2022; 23(2): 141-161.
30. Kračun D, Lopes LR, Cifuentes-Pagano E and Pagano PJ: NADPH oxidases: redox regulation of cell homeostasis and disease. Physiological Reviews 2025; 105(3): 1291-1428.
31. Blaikie L, Kay G, Maciel P and Lin PKT: Experimental modelling of Alzheimer’s disease for therapeutic screening. European Journal of Medicinal Chemistry Reports 2022; 100044.
32. Shan HM, Zang M, Zhang Q, Shi RB, Shi XJ, Mamtilahun M, Liu C, Luo LL, Tian X, Zhang Z and Yang GY: Farnesoid X receptor knockout protects brain against ischemic injury through reducing neuronal apoptosis in mice. Journal of Neuroinflammation 2020; 17(1): 1-12.
33. Panzitt K, Zollner G, Marschall HU and Wagner M: Recent advances on FXR-targeting therapeutics. Molecular and Cellular Endocrinology 2022; 552: 111678.
34. Luo C, Urgard E, Vooder T and Metspalu A: The role of COX-2 and Nrf2/ARE in anti-inflammation and antioxidative stress: aging and anti-aging. Med Hypotheses 2011; 77:174–17.
35. Kim J, Cha YN and Surh YJ: A protective role of nuclear factor-erythroid 2- related factor-2 (Nrf2) in inflammatory disorders. Mutat Res 2010; 690: 12–23.
36. Kulkarni SR, Donepudi AC, Xu J, Wei W, Cheng QC, Driscoll MV, Johnson DA, Johnson JA, Li X and Slitt AL: Fasting induces nuclear factor E2-related factor 2 and ATP-binding Cassette transporters via protein kinase A and Sirtuin- 1 in mouse and human. Antioxid. Redox Signal 2014; 20: 15–30.
37. Wang F, Pu C, Zhou P, Wang P, Liang D, Wang Q, Hu Y, Li B and Hao X: Cinnamaldehyde prevents endothelial dysfunction induced by high glucose by activating Nrf2. Cellular Physiology and Biochemistry 2015; 36(1): 315-324.
    

    ---

    How to cite this article:

    Sharma M, Sharma N and Sharma A: Alzheimer’s disease: pathological hallmarks of alzheimer’s disease. Int J Pharm Sci & Res 2025; 16(12): 3285-91. doi: 10.13040/IJPSR.0975-8232.16(12).3285-91.

    ---

    All © 2025 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.