Amyloid-Beta Plaque Formation in Alzheimer's Disease
Plaque buildup in Alzheimer's disease occurs through the extracellular accumulation of β-amyloid (Aβ) peptides, which are generated when amyloid precursor protein (APP) is cleaved by beta-secretase and gamma-secretase enzymes, leading to the formation of senile plaques that follow a distinct regional progression across the brain. 1
Molecular Mechanism of Aβ Generation
Aβ peptides are produced through the amyloidogenic processing pathway of APP, where beta-secretase (BACE-1) first cleaves APP, followed by gamma-secretase (part of the presenilin complex), generating various Aβ isoforms 2, 3
The Aβ(1-42) isoform plays the most pivotal role in AD pathogenesis due to its biochemical properties that favor aggregation into insoluble oligomers and protofibrils 3
This represents a metabolic shift away from the normal secretory pathway of APP processing, driven by genetic factors (APP mutations, presenilin mutations, APOE ε4), age-related changes, and environmental factors 1, 3
Plaque Formation and Progression
Aβ peptides aggregate into oligomers, then protofibrils, and finally into fibrillary species that accumulate as extracellular senile plaques 4, 3
Plaque accumulation follows the Thal phases, progressing through distinct brain regions in a predictable pattern as AD advances, which can be staged on a four-point scale 1
A subset of senile plaques called neuritic plaques are particularly associated with neuronal injury, characterized by dystrophic neurites that frequently contain phosphorylated tau protein 1
Neuritic Plaque Development
APP accumulation occurs in dystrophic neurites within senile plaques prior to tau accumulation, suggesting this is an early event in neuritic dystrophy 5
In non-demented individuals with plaques but without neurofibrillary pathology, dystrophic neurites show only APP accumulation, while in AD patients, these neurites also show ubiquitin, tau, and phosphorylated neurofilaments 5
The presence of tau and neurofilament epitopes in plaque neurites correlates with the extent of neurofibrillary pathology in surrounding brain tissue, indicating these are distinct but related phenomena 5
Temporal Sequence and Clinical Correlation
Aβ accumulation is considered one of the earliest measurable stages in the AD pathophysiological continuum, potentially preceding clinical symptoms by years or even decades 1
The overproduction and accumulation of Aβ must reach a critical threshold before triggering the downstream amyloid cascade that leads to neuronal dysfunction 3
However, the exact relationship between Aβ plaques and neuronal death remains debated, as histopathologic studies show poor correlation between plaque burden and neuronal/synaptic loss 6
Important Caveats
While Aβ deposition is required for AD diagnosis, oligomeric forms may be more synaptotoxic than fibrillar plaques, and current biomarkers primarily detect fibrillar Aβ rather than potentially more toxic oligomeric species 1
Some investigators propose that sequestration of Aβ into fibrillar plaques may actually be protective against more toxic oligomeric forms 1
Alternative theories suggest that intracellular events during APP processing or extraneuronal preplaque Aβ oligomers may be more important than the plaques themselves in causing neuronal death 6
The failure of Aβ-lowering therapies to demonstrate clinical benefit raises questions about whether Aβ is the primary etiologic agent or whether upstream pathophysiological events remain undiscovered 1