Autophagy Dynamics in Alzheimer’s Disease Pathogenesis

Alzheimer’s disease is characterised by progressive accumulation of amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau. Autophagy, the cell’s principal pathway for degrading and recycling misfolded proteins and damaged organelles, plays a pivotal role in maintaining neuronal homeostasis. In healthy neurons, autophagosomes envelop toxic protein aggregates and fuse with lysosomes to enable their clearance. In Alzheimer’s disease, however, autophagic flux is disrupted at multiple stages—from phagophore initiation and autophagosome formation to lysosomal degradation—leading to the build-up of autophagic vacuoles and exacerbation of amyloid and tau pathology.

Dysfunctional autophagy contributes to synaptic failure, neuroinflammation and neuronal loss. Genetic and pharmacological studies have highlighted key regulators such as the mTOR signalling axis, Beclin 1–PI3K class III complex and NRBF2, whose altered expression or activity correlates with disease severity. Microglial autophagy also influences amyloid clearance and inflammatory responses, linking immune dysfunction to autophagic defects. Restoring efficient autophagic flux emerges as a promising strategy to attenuate protein aggregation, reduce neuroinflammation and improve cognitive resilience in Alzheimer’s disease.

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Autophagy Dynamics in Alzheimer’s Disease Pathogenesis publication trend

The graph below shows the total number of articles in autophagy dynamics in alzheimer’s disease pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Autophagy: Intracellular pathway for degradation and recycling of proteins and organelles via autophagosomes and lysosomes.

Amyloid β (Aβ): Peptide fragment derived from amyloid precursor protein that aggregates into extracellular plaques in Alzheimer’s disease.

Tau: Microtubule-associated neuronal protein whose hyperphosphorylated form forms intracellular neurofibrillary tangles.

mTOR pathway: Nutrient-sensitive kinase signalling cascade that inhibits autophagy when activated.

Microglia: Resident immune cells of the central nervous system responsible for debris clearance and inflammatory responses.

NRBF2: Regulatory subunit of the Beclin 1 class III PI3K complex essential for autophagosome formation and maturation.

References

1. Cyanidin-3-O-glucoside protects the brain and improves cognitive function in APPswe/PS1ΔE9 transgenic mice model. Journal of Neuroinflammation (2023).
2. Molecular Regulation Mechanism of Microglial Autophagy in the Pathology of Alzheimer's Disease. Aging and Disease (2023).
3. Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications. Frontiers in Aging Neuroscience (2018).
4. Autophagy protein NRBF2 has reduced expression in Alzheimer’s brains and modulates memory and amyloid-beta homeostasis in mice. Molecular Neurodegeneration (2019).