The functional role of the retromer complex in the pathogenesis of Alzheimer's disease in Down syndrome
[article]
(:Unkn) Unknown, University, My, Domenico Pratico
2022
Down syndrome (DS) is a congenital disorder caused by partial or complete triplication of human chromosome 21. By age 40, nearly all individuals with DS develop amyloid beta (Aβ) plaques and tau neurofibrillary tangles, the pathological hallmarks of Alzheimer's disease (AD). This increased susceptibility to Alzheimer's Disease in Down syndrome (AD-DS) has primarily been attributed to an over-dosage of the amyloid precursor protein (APP), which generates neurotoxic Aβ fragments when cleaved by
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... secretase. However, the complete molecular mechanisms of AD-DS are not completely understood, as trisomy of chromosome 21 can induce AD-like neuropathology independently of APP triplication. In addition to classical AD neuropathology, enlarged, APP-positive early endosomes appear early in AD-DS pathogenesis and are the first site of Aβ accumulation. In AD, these endocytic abnormalities have been linked to dysfunction of the endosomal-sorting system known as the retromer complex. Mechanistically, retromer dysfunction can influence amyloid beta production by increasing interaction of the retromer cargo APP with beta-secretase. However, recent studies have also implicated the retromer complex in the development of tau pathology, both through regulation of tau phosphorylation and degradation via lysosomes. Given that retromer dysfunction is associated with the endosomal phenotype found in AD-DS, and that the retromer system can modulate key aspects of AD-DS neuropathology, the objective of the current study is to investigate the role of the retromer complex in the development of AD-DS. We first examined the retromer system in cortices and hippocampi from human patients with DS. Retromer recognition core proteins were significantly decreased in both the hippocampi and cortices of young and aged DS subjects compared to controls. Correlative analyses showed a significant inverse relationship between recognition core proteins and levels of soluble forms of A 1-40 and 1-42 in both hippocampus and cortex tissue, and phosphorylated [...]
doi:10.34944/dspace/7636
fatcat:lmn2hfyaufagniarj4an7td4vy