Bin1 and CD 2 AP polarise the endocytic generation of beta‐amyloid

Abstract

The mechanisms driving pathological beta-amyloid (Ab) generation in late-onset Alzheimer's disease (AD) are unclear. Two late-onset AD risk factors, Bin1 and CD2AP, are regulators of endocytic trafficking, but it is unclear how their endocytic function regulates Ab generation in neurons. We identify a novel neuron-specific polarisation of Ab generation controlled by Bin1 and CD2AP. We discover that Bin1 and CD2AP control Ab generation in axonal and dendritic early endosomes, respectively. Both Bin1 loss of function and CD2AP loss of function raise Ab generation by increasing APP and BACE1 convergence in early endosomes, however via distinct sorting events. When Bin1 levels are reduced, BACE1 is trapped in tubules of early endosomes and fails to recycle in axons. When CD2AP levels are reduced, APP is trapped at the limiting membrane of early endosomes and fails to be sorted for degradation in dendrites. Hence, Bin1 and CD2AP keep APP and BACE1 apart in early endosomes by distinct mechanisms in axon and dendrites. Individuals carrying variants of either factor would slowly accumulate Ab in neurons increasing the risk for late-onset AD.

Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons

“…Strikingly SorLA, Bin1, PICALM, and CD2AP, which are linked to increased risk for late onset AD [65,66], all have functions related to endocytosis and endosome trafficking. Ubelmann et al have already shown that depletion of CD2AP inhibits APP and/or CTFs sorting towards ILVs and concomitantly increases Aβ production in post-synaptic endosomes [67]. Exosomal proteins released by neurons within few minutes represent an easily accessible sampling of ILVs.…”

Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer’s Disease

“…At the same time, however, this class of genes has a secondary consequence of increasing intracellular APP fragments by regulating the levels of APP and/or BACE1 in the early endosome (Dumanis et al, 2015; Fjorback et al, 2012; Miyagawa et al, 2016; Ubelmann et al, 2016) and APP’s amyloidogenic cleavage (Andersen et al, 2005; Dumanis et al, 2015; Fjorback et al, 2012; Miyagawa et al, 2016; Offe et al, 2006; Rogaeva et al, 2007; Thomas et al, 2016; Ubelmann et al, 2016; Xiao et al, 2012) (Fig. 1).…”

Analysis of Aβ_x-42/Aβ_x-40 and Tau upon siRNA-mediated downregulation of APOE, BIN1, PICALM, CLU, PRNP and CST3 in wildtype mouse primary neurons

“…It is conceivable that the reason why we did not observe any effects of APOE knockdown on Aβ x-40 and Aβ x-42 is because it is expressed mainly by astrocytes and produced only at low amounts by primary neuronal cultures as used for our study. For BIN1, conflicting results have been reported on its role in Aβ regulation: while depletion of BIN1 in neurons resulted in a slight decrease in secreted Aβ 40 with a concomitant increase in intracellular Aβ 40 and Aβ 42 in one study [33], increased levels of secreted Aβ were observed by another group [34] and no effects were detected in neuroblastoma cells in a third study [35]. Similarly, also for PICALM the observed effects on Aβ are diverging: in one study, PICALM was reported to promote Aβ generation in cells and to accelerate Aβ pathology in APP transgenic mice [36] whereas another study observed no effect on cellular Aβ production [37].…”