Molecular Mechanisms in Alzheimer's Disease Pathogenesis

Alzheimer’s disease is characterised by the progressive accumulation of misfolded proteins and the ensuing disruption of neuronal networks. Central to its pathogenesis are extracellular plaques composed of amyloid β peptides and intracellular tangles of hyperphosphorylated tau. Aberrant processing of the amyloid precursor protein by secretases and age‐dependent activation of asparagine endopeptidase drive amyloidogenic pathways, while dysregulated kinases promote tau phosphorylation and aggregation. Microglial cells respond to these deposits by adopting proinflammatory phenotypes that amplify synaptic dysfunction and neuronal loss. Concurrent alterations in lipid metabolism, mitochondrial function and lysosomal clearance further compromise cellular homeostasis. Genetic risk factors and transcriptional regulators link inflammatory signalling to protease expression, forging a feed-forward cycle of pathology. Emerging insights into the gut–brain axis implicate microbial metabolites in modulating microglial activation. Together, these molecular pathways converge on synaptic integrity, offering multiple points for therapeutic intervention and a framework for understanding global disease burden.

Research from Nature Portfolio

Recent studies have demonstrated that specific gut bacteria influence neuroinflammation and amyloid pathology via polyunsaturated fatty acid metabolites. In experimental models, metabolites such as 12-HHTrE and prostaglandin E2 were shown to activate microglia through transcriptional pathways that potentiate amyloid and tau aggregation, linking gut dysbiosis to central nervous system pathology. Parallel work has elucidated the role of delta-secretase (asparagine endopeptidase) as an age-regulated protease cleaving both amyloid precursor protein and tau. Inhibition of this enzyme in transgenic mice reduces plaque and tangle burden, restores synaptic plasticity and rescues cognitive deficits. Further research has identified C/EBPβ as a pivotal transcription factor that upregulates delta-secretase and inflammatory mediators in an age-dependent manner; modulation of C/EBPβ expression attenuates protease activity and ameliorates disease features.

Molecular Mechanisms in Alzheimer's Disease Pathogenesis publication trend

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

Technical terms

Amyloid β (Aβ): peptide derived from amyloid precursor protein that aggregates into extracellular plaques.

Hyperphosphorylated tau: modified microtubule-associated protein that forms intracellular neurofibrillary tangles.

Microglia: resident immune cells of the brain that mediate inflammatory and phagocytic responses.

Delta-secretase (asparagine endopeptidase): lysosomal cysteine protease that cleaves APP and tau in an age-dependent manner, promoting pathology.

PPARα: nuclear receptor regulating lipid metabolism and inflammation, facilitating microglial clearance of Aβ.

TFEB: master transcription factor of the autophagy–lysosomal pathway, coordinating cellular clearance mechanisms.

C/EBPβ: inflammation-regulated transcription factor that controls expression of delta-secretase and cytokines in ageing brain.

References

1. Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease. Nature Communications (2015).
2. Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease. Nature Communications (2017).
3. C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer’s disease. Nature Communications (2018).
4. Oleoylethanolamide facilitates PPARα and TFEB signaling and attenuates Aβ pathology in a mouse model of Alzheimer’s disease. Molecular Neurodegeneration (2023).
5. A novel transgenic mouse line with hippocampus-dominant and inducible expression of truncated human tau. Translational Neurodegeneration (2023).
6. A small molecule transcription factor EB activator ameliorates beta‐amyloid precursor protein and Tau pathology in Alzheimer's disease models. Aging Cell (2019).