Neurology Central

Cause of Alzheimer’s-related plaques linked to endocytic pathway abnormalities

Researchers from the University of California (UC; CA, USA) have demonstrated that protein abnormalities in the endocytic pathway may be linked to the axonal dysfunction and degeneration seen in Alzheimer’s disease (AD) and Down Syndrome (DS).

AD and DS are characterized by amyloid plaques and neurofibrillary tangles; however, these manifestations are not detectable until the later stages of the disease. Some researchers believe that for successful treatment earlier disease characteristics must be targeted. Previous studies have highlighted dysfunction in the endocytic pathway as a precursor to AD, though the cause of this has not been identified.

This new study, published recently in the Journal of Clinical Investigation, indicates that abnormally active Rab5 may result in enlarged endosomes and contribute to abnormal endocytic processes, leading to the onset of dementia and appearance of typical AD pathologies.

The team demonstrated that an increased accumulation of amyloid precursor protein (APP) in neurons increases Rab5 activation, leading to early endosome enlargement. This results in disruption of retrograde axonal transport of NGF, which is thought to cause functional abnormalities in affected neurons.

The functional impacts of APP accumulation on the endocytic pathway and the ensuing decline in NGF signaling and axonal trafficking were observed in cultured PC12 cells, as well as cultured rat basal forebrain cholinergic neurons and basal forebrain cholinergic neurons from a DS mouse model.

Interestingly, the researchers also demonstrated that when a dominant-negative Rab5 mutant construct is expressed in Drosophila, APP-induced axonal blockage was significantly reduced.

They conclude that increased APP may impact the endocytic pathway to disrupt trophic signaling, resulting in axonal dysfunction.

Chengbiao Wu, UC San Diego School of Medicine (CA, USA), commented: “Our current study highlights the significance of abnormally active Rab5 protein as a key contributor to early development of [AD]. We believe this will open new possibilities for understanding the disease and for developing novel and effective therapies.”

Sources: Xu W, Weissmiller A, White J et al. Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration. ‎J. Clin. Invest. 126(5) 1–41. DOI: 10.1172/jci82409  (2016); UC San Diego Health press release