Apolipoprotein E4 domain interaction: Synaptic and cognitive deficits in mice

Background: Apolipoprotein E4 (apoE4), the major genetic risk factor for Alzheimer's disease (AD) and other neurodegenerative diseases, has three structural and biophysical properties that distinguish it from the other isoforms-domain interaction, reduced stability, and lack of cysteine. Assessing their relative contributions to effects of apoE4-associated pathogenesis in AD is important from a mechanistic and therapeutic perspective, that is not possible using human apoE transgene or knock-in models. Methods: We analyzed Arg-61 apoE mice, a gene-targeted model that selectively displays domain interaction. Results: The mice displayed age-dependent loss of the synaptic protein synaptophysin in neocortex and hippocampus and had lower levels of the postsynaptic neuroligin-1. Activation of dentate gyrus granule neurons increased Arc expression 3.5-fold in wildtype mice but only 2.3-fold in Arg-61 mice. The losses of synaptic proteins caused a mild memory deficit in Arg-61 mice in the water-maze test. Since synaptic integrity requires efficient glutamate uptake, we measured astrocyte glutamate transporter I in the hippocarnpus. The level was reduced in Arg-61 mice, suggesting that inefficient glutamate uptake by astrocytes causes chronic excitotoxicity. Consistent with the reduced secretion of Arg-61 apoE by astrocytes in this model, cholesterol secretion was also reduced 34%. This reduction could also contribute to the synaptic deficits by limiting the availability of cholesterol for neuronal repair. Conclusions: Domain interaction in the absence of other structural characteristics of apoE4 is sufficient to cause synaptic pathology and functional synaptic deficits, potentially associated with astrocyte dysfunction and impaired maintenance of neurons. Therapeutic targeting of domain interaction might blunt effects of apoE4 in neurodegenerative disease. (C) 2008 The Alzheimer's Association. All rights reserved.