Amyloid Cascade & Tau Pathology

The amyloid cascade hypothesis proposes that amyloid-β accumulation triggers tau hyperphosphorylation, neurofibrillary tangles, and neuronal death — the defining pathology of Alzheimer's disease.

Overview

Amyloid precursor protein (APP) is sequentially cleaved by β-secretase (BACE1) and γ-secretase to produce Aβ peptides. Aβ42 is most aggregation-prone, forming soluble oligomers (most toxic), protofibrils, and eventually insoluble amyloid plaques. Downstream, Aβ triggers tau hyperphosphorylation by GSK3β and CDK5 kinases. Hyperphosphorylated tau detaches from microtubules, forms paired helical filaments (PHFs), and aggregates into neurofibrillary tangles (NFTs). NFT burden correlates more closely with cognitive decline than plaque load.

Key Steps

1. APP is cleaved by BACE1 at the β-site, then by γ-secretase (presenilin) at multiple sites
2. Aβ42 (42 amino acids) is produced at lower abundance than Aβ40 but is far more aggregation-prone
3. Aβ42 oligomers form — small soluble assemblies that are the primary synaptotoxic species
4. Oligomers impair LTP, activate microglia, and trigger tau kinase cascades (GSK3β, CDK5)
5. Hyperphosphorylated tau dissociates from microtubules, forms PHFs and NFTs
6. Tau pathology spreads trans-synaptically in a stereotyped pattern (entorhinal → hippocampus → neocortex)

Disease Relevance

• Alzheimer's: Anti-Aβ antibodies (lecanemab, donanemab) show modest clinical benefit. Tau-targeting ASOs (BIIB080) and tau immunotherapy are advancing. The field increasingly recognizes that both amyloid and tau must be addressed.

Therapeutic Targets

• Lecanemab: Binds Aβ protofibrils → microglial phagocytosis → plaque clearance
• Donanemab: Targets N-truncated pyroglutamate Aβ in established plaques
• Curcumin: Binds Aβ fibrils, inhibits aggregation, and reduces tau phosphorylation
• Methylene Blue: Inhibits tau aggregation via cysteine oxidation in tau repeat domains