APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer's disease: a systematic review
ALZHEIMERS RESEARCH & THERAPY
Authors: Emrani, Sheina; Arain, Hirra A.; DeMarshall, Cassandra; Nuriel, Tal
Abstract
Possession of the epsilon 4 allele of apolipoprotein E (APOE) is the primary genetic risk factor for the sporadic form of Alzheimer's disease (AD). While researchers have extensively characterized the impact that APOE epsilon 4 (APOE4) has on the susceptibility of AD, far fewer studies have investigated the phenotypic differences of patients with AD who are APOE4 carriers vs. those who are non-carriers. In order to understand these differences, we performed a qualitative systematic literature review of the reported cognitive and pathological differences between APOE4-positive (APOE4+) vs. APOE4-negative (APOE4-) AD patients. The studies performed on this topic to date suggest that APOE4 is not only an important mediator of AD susceptibility, but that it likely confers specific phenotypic heterogeneity in AD presentation, as well. Specifically, APOE4+ AD patients appear to possess more tau accumulation and brain atrophy in the medial temporal lobe, resulting in greater memory impairment, compared to APOE4- AD patients. On the other hand, APOE4- AD patients appear to possess more tau accumulation and brain atrophy in the frontal and parietal lobes, resulting in greater impairment in executive function, visuospatial abilities, and language, compared to APOE4+ AD patients. Although more work is necessary to validate and interrogate these findings, these initial observations of pathological and cognitive heterogeneity between APOE4+ vs. APOE4- AD patients suggest that there is a fundamental divergence in AD manifestation related to APOE genotype, which may have important implications in regard to the therapeutic treatment of these two patient populations.
GSK3 alpha, not GSK3 beta, drives hippocampal NMDAR-dependent LTD via tau-mediated spine anchoring
EMBO JOURNAL
Authors: Draffin, Jonathan E.; Sanchez-Castillo, Carla; Fernandez-Rodrigo, Alba; Sanchez-Saez, Xavier; Avila, Jesus; Wagner, Florence F.; Esteban, Jose A.
Abstract
Glycogen synthase kinase-3 (GSK3) is an important signalling protein in the brain and modulates different forms of synaptic plasticity. Neuronal functions of GSK3 are typically attributed to one of its two isoforms, GSK3 beta, simply because of its prevalent expression in the brain. Consequently, the importance of isoform-specific functions of GSK3 in synaptic plasticity has not been fully explored. We now directly address this question for NMDA receptor-dependent long-term depression (LTD) in the hippocampus. Here, we specifically target the GSK3 isoforms with shRNA knock-down in mouse hippocampus and with novel isoform-selective drugs to dissect their roles in LTD. Using electrophysiological and live imaging approaches, we find that GSK3 alpha, but not GSK3 beta, is required for LTD. The specific engagement of GSK3 alpha occurs via its transient anchoring in dendritic spines during LTD induction. We find that the major GSK3 substrate, the microtubule-binding protein tau, is required for this spine anchoring of GSK3 alpha and mediates GSK3 alpha-induced LTD. These results link GSK3 alpha and tau in a common mechanism for synaptic depression and rule out a major role for GSK3 beta in this process.
COA
Publication 
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