Ning Zhong and Karl H. Weisgraber Pages 415 - 418 ( 4 )
Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimers disease (AD) by an as yet to be defined mechanism. Since the structure or biophysical properties of a protein directly determines function, our approach to addressing mechanism is structure:function based. Domain interaction a structural property of apoE4 that distinguishes it from apoE3 is predicted to contribute to the association of apoE4 with AD. We developed a mouse model, the Arg-61 apoE model, which is specific for domain interaction. These mice display synaptic, functional, and cognitive deficits, demonstrating domain interaction is the causative factor. We present evidence that domain interaction results in stressed astrocytes that are dysfunctional and propose that dysfunctional astrocytes are an early player in apoE4-associated AD and that domain interaction is a potential therapeutic target., Understanding, the, Basis, for, the, Association, of, apoE4, with, Alzheimers, Disease:, Opening, the, Door, for, Therapeutic, Approaches
Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA.