This hypothesis addresses the critical role of amyloid plaque and neurofibrillary tangle (NFT) deposition in accurately modeling Alzheimer's disease (AD) in mouse models. The presence of both pathological hallmarks is considered essential for creating preclinical models that faithfully recapitulate key features of human AD neuropathology[1].
Type: Mechanistic Proposal
Confidence: Supported
Related Diseases: Alzheimer's Disease
Amyloid plaques are extracellular aggregates of amyloid-beta (Aβ) peptides, derived from the amyloid precursor protein (APP) through proteolytic cleavage by β-secretase (BACE1) and γ-secretase. The accumulation of Aβ42 and Aβ40 peptides into plaques is considered an early event in AD pathogenesis, triggering downstream tau pathology and neuroinflammation[2].
Neurofibrillary tangles are intracellular inclusions composed of hyperphosphorylated tau protein. Tau normally stabilizes microtubules, but when phosphorylated at abnormal sites, it aggregates into paired helical filaments (PHFs) that disrupt neuronal transport and lead to cell death. The progression of NFT pathology follows a predictable pattern in AD, beginning in the entorhinal cortex and spreading through the hippocampus and neocortex[3].
The amyloid cascade hypothesis posits that Aβ accumulation is the primary initiating event in AD, leading to tau pathology, synaptic loss, and neuronal death. According to this model:
However, recent evidence suggests a more complex relationship, with bidirectional interactions between amyloid and tau pathology[4].
Accurate AD mouse models must replicate key pathological features:
While most mouse models use familial AD (FAD) mutations, genetic risk factors for sporadic AD include:
These risk factors suggest that sporadic AD may involve mechanisms beyond simple Aβ accumulation[5].
This hypothesis is supported by multiple lines of evidence from the literature. However, recent clinical trials targeting amyloid have shown that removing plaques alone may not halt cognitive decline, highlighting the importance of understanding tau pathology and other contributing factors.
Understanding the relationship between amyloid and tau has critical implications for therapy: