Impaired intracellular trafficking triggers Alzheimer’s disease
AD is characterised by an aberrant accumulation of beta-amyloid (Aβ) at neuronal synapses, leading to dysfunction and rendering difficult the formation of new synapses. This leads to memory loss in patients suffering from the disease. In normal brains, Aβ is present as a product of neuronal metabolism, indicating that it has a physiological function. It is derived through proteolytic processing of the amyloid precursor protein (APP) by enzymes known as secretases and is either secreted or retained in endosomes near synapses. Given that temporal and subcellular localisation of APP is different from its proteolytic secretases, it is intracellular trafficking of APP that determines its degradation. Emerging evidence suggests that Aβ accumulation is associated with impaired intracellular trafficking, with cells being unable to clear Aβ through lysosomes. However, it remains unknown how the complex geometry, polarity, and aging of neurons can influence APP trafficking. The EU-funded TRAFFICINAD project investigated the mechanism underlying neuronal intracellular trafficking and how it causes Aβ accumulation that leads to AD. Considering that ageing diminishes the ability to sustain learning and memory and is linked to AD development, scientists investigated how intracellular trafficking is altered with age. Researchers focused on the role of two late-onset AD risk factors – Bin1 and CD2AP in the endocytic localisation of APP and of beta-secretase. They discovered that loss of function of either of those two factors affected Aβ generation in dendrites or axons. Both Bin1 and CD2AP were localised in endosomes but functioned through separate mechanisms, with the latter affecting APP sorting into late endosomes. Collectively, these observations established Bin1 and CD2AP as regulators of intracellular trafficking pathways relevant for the processing of APP. The TRAFFICINAD study has highlighted the importance of delineating the cellular mechanisms of neuronal intracellular trafficking as a means of understanding late-onset AD.
Keywords
Alzheimer’s disease, TRAFFICINAD, beta-amyloid, Bin1, CD2AP
