Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is the foremost cause of global dementia, also characterized by retinal changes involving Aβ, hyperphosphorylated-tau (p-tau), neuronal degeneration, and tissue atrophy. Mitochondrial-driven reactive oxygen species (ROS) production, linked to synaptic dysfunction, is common to various neurodegenerative conditions, including AD. Despite synaptic dysfunction being an early predictor of cognitive decline in AD, its occurrence in the AD retina is unexplored.

Basic Science and Pathogenesis.

Background: This study identifies and quantifies diverse pathological tau forms in the retina at both early and advanced stages of Alzheimer's disease (AD) and assesses their correlation with disease status. In the pathogenesis of AD, the tau protein undergoes post-translational modifications, including hyperphosphorylation (p-tau). As the disease progresses, pathological tau can propagate as oligomers, aggregate into fibrils, and paired helical filaments (PHF), and ultimately form intraneuronal neurofibrillary tangles (NFTs).

deletion and a rare variant associated with late onset Alzheimer's disease trigger BACE1 accumulation in axonal swellings.

Axonal dystrophy, indicative of perturbed axonal transport, occurs early during Alzheimer's disease (AD) pathogenesis. Little is known about the mechanisms underlying this initial sign of the pathology. This study proves that Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) loss of function, due to genetic deletion or a rare variant that cosegregates with late-onset AD, disrupts the axonal trafficking of the β-site APP-cleaving enzyme 1 (BACE1) resulting in its accumulation in axonal swellings in cultured neurons and in vivo.