Detrimental effects of apolipoprotein E4: potential therapeutic targets in Alzheimer's disease.
As the major genetic risk factor for Alzheimer's disease, the apolipoprotein (apo) E4 isoform is a promising therapeutic target. ApoE4 likely contributes to Alzheimer's disease pathology by interacting with multiple factors through various pathways. Interactions with the amyloid beta peptide and the amyloid cascade, for example, may lead to cognitive decline and neurodegeneration. Alternatively, apoE4 might act independently of the amyloid beta peptide. Our working hypothesis is that apoE has isoform-specific effects on neuronal repair and remodeling. One or more injurious agents could result in neuronal damage, requiring neuronal repair or remodeling. The injurious agents (or "second hits") may be genetic, metabolic, or environmental. Potential therapeutic strategies include changing the structure of apoE4 to be more apoE3-like, inhibiting the protease that cleaves apoE4 into toxic fragments, and protecting mitochondria from apoE4 toxicity. Structural features that distinguish apoE4 and apoE3 determine their functional differences and hold the key to understanding how apoE4 is involved in Alzheimer's disease.
Mahley
Robert W
RW
Gladstone Institute of Neurological Disease 1650 Owens Street, San Francisco, CA 94158, USA. rmahley@gladstone.ucsf.edu
Huang
Yadong
Y
Weisgraber
Karl H
KH
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D053327:Apolipoprotein E4 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans
D014150:Antipsychotic Agents; D053327:Apolipoprotein E4