Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes.

The strongest genetic risk factor influencing susceptibility to late-onset Alzheimer's disease (AD) is apolipoprotein E (APOE) genotype. APOE has three common isoforms in humans, E2, E3, and E4. The presence of two copies of the E4 allele increases risk by ∼12-fold whereas E2 allele is associated with an ∼twofold decreased risk for AD. These data put APOE central to AD pathophysiology, but it is not yet clear how APOE alleles modify AD risk. Recently we found that astrocytes, a major central nervous system cell type that produces APOE, are highly phagocytic and participate in normal synapse pruning and turnover. Here, we report a novel role for APOE in controlling the phagocytic capacity of astrocytes that is highly dependent on APOE isoform. APOE2 enhances the rate of phagocytosis of synapses by astrocytes, whereas APO4 decreases it. We also found that the amount of C1q protein accumulation in hippocampus, which may represent the accumulation of senescent synapses with enhanced vulnerability to complement-mediated degeneration, is highly dependent on APOE alleles: C1q accumulation was significantly reduced in APOE2 knock-in (KI) animals and was significantly increased in APOE4 KI animals compared with APOE3 KI animals. These studies reveal a novel allele-dependent role for APOE in regulating the rate of synapse pruning by astrocytes. They also suggest the hypothesis that AD susceptibility of APOE4 may originate in part from defective phagocytic capacity of astrocytes which accelerates the rate of accumulation of C1q-coated senescent synapses, enhancing synaptic vulnerability to classical-complement-cascade mediated neurodegeneration.

APOE genotype and stress response - a mini review.

The APOE gene is one of currently only two genes that have consistently been associated with longevity. Apolipoprotein E (APOE) is a plasma protein which plays an important role in lipid and lipoprotein metabolism. In humans, there are three major APOE isoforms, designated APOE2, APOE3, and APOE4. Of these three isoforms, APOE3 is most common while APOE4 was shown to be associated with age-related diseases, including cardiovascular and Alzheimer's disease, and therefore an increased mortality risk with advanced age. Evidence accumulates, showing that oxidative stress and, correspondingly, mitochondrial function is affected in an APOE isoform-dependent manner. Accordingly, several stress response pathways implicated in the aging process, including the endoplasmic reticulum stress response and immune function, appear to be influenced by the APOE genotype. The investigation and development of treatment strategies targeting APOE4 have not resolved any therapeutic yet that could be entirely recommended. This mini-review provides an overview on the state of research concerning the impact of the APOE genotype on stress response-related processes, emphasizing the strong interconnection between mitochondrial function, endoplasmic reticulum stress and the immune response. Furthermore, this review addresses potential treatment strategies and associated pitfalls as well as lifestyle interventions that could benefit people with an at risk APOE4 genotype.