β-amyloid precursor protein (APP) and its cleaved products are strongly implicated in Alzheimer’s Disease (AD). Endosomes are highly active APP processing sites and endosome anomalies associated with upregulated expression of early endosomal regulator, rab5, are the earliest known disease-specific neuronal response in AD. Here, we show that the rab5 effector APPL1 mediates rab5 over-activation in Down Syndrome (DS) and AD, which is caused by elevated levels of the β-cleaved carboxy-terminal fragment of APP (βCTF). βCTF recruits APPL1 to rab5 endosomes, where it stabilizes active GTP-rab5, leading to pathologically accelerated endocytosis, endosome swelling, and selectively impaired axonal transport of rab5 endosomes. In DS fibroblasts, APPL1 knockdown corrects these endosomal anomalies. βCTF levels are also elevated in Alzheimer brain, which is accompanied by abnormally high recruitment of APPL1 to rab5 endosomes as seen in DS fibroblasts. These studies indicate that persistent rab5 over-activation through βCTF-APPL1 interactions constitutes a novel APP-dependent pathogenic pathway in AD.

Kim and Ziff examine the molecular mechanism of synaptic scaling, showing that inhibition of neuronal excitability reduces calcium influx into neurons, resulting in decreased calcineurin activity. This leads to increased surface expression of calcium-permeable AMPA receptors as a homeostatic response.

Gene knockout (KO) does not always result in phenotypic changes, possibly due to mechanisms of functional compensation. We have studied mice lacking cGMP-dependent kinase II (cGKII), which phosphorylates GluA1, a subunit of AMPA receptors (AMPARs), and promotes hippocampal long-term potentiation (LTP) through AMPAR trafficking. Acute cGKII inhibition significantly reduces LTP, whereas cGKII KO mice show no LTP impairment. Significantly, the closely related kinase, cGKI, does not compensate for cGKII KO. Here, we describe a previously unidentified pathway in the KO hippocampus that provides functional compensation for the LTP impairment observed when cGKII is acutely inhibited. We found that in cultured cGKII KO hippocampal neurons, cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors was decreased, reducing cytoplasmic Ca 2+ signals. This led to a reduction of calcineurin activity, thereby stabilizing GluA1 phosphorylation and promoting synaptic expression of Ca 2+ -permeable AMPARs, which in turn induced a previously unidentified form of LTP as a compensatory response in the KO hippocampus. Calcineurin-dependent Ca 2+ -permeable AMPAR expression observed here is also used during activity-dependent homeostatic synaptic plasticity. Thus, a homeostatic mechanism used during activity reduction provides functional compensation for gene KO in the cGKII KO hippocampus.LTP | Ca 2+ -permeable AMPA receptors | gene knockout | calcineurin

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Highlights d Pathological Rab5 activation in PA-Rab5 mice mimics AD-like endosomal dysfunction d PA-Rab5 mice have synaptic function/structure deficits and GSK-3b-mediated tauopathy d Rab5 overactivation in vivo underlies cholinergic degeneration and memory deficits d Endosomal dysfunction alone induces prodromal and degenerative AD-related changes