Abstract
The earliest clinical manifestation of Alzheimer's disease (AD) is cognitive impairment caused by synaptic dysfunction. ApoE4, the primary risk factor for late‐onset AD, disrupts synaptic homeostasis by impairing synaptic ApoE receptor trafficking. Alternative splicing of ApoE receptor‐2 (Apoer2) maintains synaptic homeostasis. In this issue, Hinrich et al ([2016][1]) show that Apoer2 splicing is impaired in human AD brains and murine AD models and that restoring normal splicing in the mouse rescues amyloid‐induced cognitive defects. [1]: #ref-3
Highlights
The earliest clinical manifestation of Alzheimer’s disease (AD) is cognitive impairment caused by synaptic dysfunction
Another mechanism by which oligomeric Ab weakens the synapse is through the activation of metabotropic glutamate receptors, which induce long-term depression (LTD) through the expression of the phosphatase STEP and dephosphorylation of NMDA receptors on their cytosolic domains
Both mechanisms result in the removal of NMDA receptors from the synapse, and this chronically increasing NMDAR hypofunction leads to the progressive synapse weakening and loss that is responsible for the early cognitive impairment
Summary
The earliest clinical manifestation of Alzheimer’s disease (AD) is cognitive impairment caused by synaptic dysfunction. Both mechanisms result in the removal of NMDA receptors from the synapse, and this chronically increasing NMDAR hypofunction leads to the progressive synapse weakening and loss that is responsible for the early cognitive impairment. The Ab-mediated suppression of LTP (and induction of LTD) is opposed by cytoplasmic signaling of an apolipoprotein E (ApoE) receptor, Apoer2, which strengthens the synapse.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
