Sumeen Gill

Background: Alzheimer’s disease (AD) is a complex multifactorial neurodegenerative disorder characterized by progressive memory loss and multiple other cognitive changes. As per a 2016 report, over 46.8 million individuals suffer from AD worldwide, and cases are projected to reach more than 131 million by 2050 ^[1]. Despite its increasing prevalence, the causal factors of AD are heavily debated. Pathologically, two hallmarks generally define AD; intracellular tau aggregates that make neurofibrillary tangles and extracellular amyloid plaques made of b-amyloid protein ^[2]. AD is also associated with several other pathological changes, including neuroinflammation, defects in cholinergic neurons, mitochondrial dysfunction, synapse loss, and neurodegeneration. Many of these changes are linked to plaque formation. In this light, AD pathology was hypothesized to result from an imbalance between the production and clearance of plaque-forming proteins ^[3]. The abnormal accumulation of proteins has been linked to abnormalities in autophagy pathways. However, the molecular basis of this dysfunction is still being uncovered ^{[4, 5]}. Current treatments for AD only provide symptomatic relief but cannot stop the progression of the disease. For example, cholinesterase inhibitors and NMDA receptor antagonists target synaptic function, and antidepressants and antipsychotics only target behavioral symptoms. By uncovering the molecular basis of plaque formation in the context of autophagy dysfunction, new therapies targeting autophagy have the promise to restrain AD progression.

Objective: This narrative explored the molecular mechanisms by which the dysregulation of autophagy leads to plaque formation in Alzheimer’s disease.

Search methods: An online search in the PubMed database was conducted from 2018 to 2023. Reviews were identified using the following keywords: “Alzheimer’s disease”, “plaque formation”, “neurodegeneration”, and “autophagy”. The primary research papers were found by utilizing the medical subject headings (MeSH) tool on PubMed and selecting “metabolism”, “therapy”, “genetics”, and “physiopathology” under “Alzheimer’s Disease”.

Results: Studies indicate that autophagy is a crucial pathway that is enhanced during cell stress and is downregulated or dysfunctional in Alzheimer’s disease (AD) ^{[2, 5]}. Using RT-PCR and immunofluorescence imaging, a study has demonstrated the downregulation of autophagy proteins ATG and LC3B in hippocampal neurons from a transgenic mouse model of AD by 1.6-2-folds compared to wild-type mouse hippocampal neurons ^[1]. Another study probed this further by using five different mouse models of AD (5xFAD, TfCRND8, PSAPP, Tg2576, and APP51a) and a neuron-specific probe of autophagy and pH (mRFP-eGFP-LC3). The study found that autolysosome acidification declines in the neurons well before plaque formation. Notably, such alteration was associated with a significant deficiency in vATPase, an enzyme that maintains the acidity of autolysosomes, in all five mouse models. An optimal acidic pH is necessary to properly degrade abnormal proteins, damaged organelles, and other cellular debris. The decline in vATPase leads to the buildup of Ab/APP- bCTF proteins in enlarged and poorly acidified autolysosomes (pa-AL). The protein-rich pa-AL was then shown to pack into large membrane blebs that form a unique pattern termed PANTHOS due to its structure akin to the poisonous flower. The quantitative analysis further confirmed that PANTHOS neurons were the principal source of senile plaques in all five AD models ^[2].

Conclusion: Overall, studies indicate that the dysregulation of autophagy is an upstream cause of protein aggregation and plaque formation in Alzheimer’s disease (AD). Specifically, the dysfunctional acidification of autolysosomes leads to the accumulation of Ab/APP-bCTF in poorly acidified autolysosomes, which then aggregate into a flower-like rosette termed PANTHOS. These PANTHOS neurons are the primary sources of senile plaques. Targeting the faulty acidification enzyme, vATPase, and downregulated autophagy proteins, could lead to novel upstream therapy for AD.

Works Cited:

1. Reddy PH, Yin X, Manczak M, et al. Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer’s disease. Hum Mol Genet. Jul 15 2018;27(14):2502-2516. doi:10.1093/hmg/ddy154
2. Lee J-H, Yang D-S, Goulbourne CN, et al. Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nature Neuroscience. 2022/06/01 2022;25(6):688-701. doi:10.1038/s41593-022-01084-8
3. Wang J, Liu B, Xu Y, et al. Activation of CREB-mediated autophagy by thioperamide ameliorates β-amyloid pathology and cognition in Alzheimer’s disease. Aging Cell. Mar 2021;20(3):e13333. doi:10.1111/acel.13333
4. Hung C, Livesey FJ. Endolysosome and autophagy dysfunction in Alzheimer disease. Autophagy. Nov 2021;17(11):3882-3883. doi:10.1080/15548627.2021.1963630
5. Zhang X, Wei M, Fan J, et al. Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons. Autophagy. Jun 2021;17(6):1519-1542. doi:10.1080/15548627.2020.1840796