Carriers of the Apolipoprotein (Apo) E4 allele, found in one-fifth of the general population, face an increased risk of developing sporadic Alzheimer’s disease (AD). However, the mechanism by which ApoE4 confers heightened risk of AD remains unclear.
Researchers in the journal PNAS tested the hypothesis that ApoE4 is tied to a loss of brain phospholipid balance. Analysis of postmortem brain tissues from ApoE4carriers revealed reduced levels of the brain metabolite phosphoinositol biphosphate (PIP2), reflecting progressively declining brain PIP2 levels with normal human aging, mild cognitive impairment, and AD.
Compared with mice carrying the ApoE3 allele, mice engineered to express ApoE4 displayed reduced PIP2 levels in hippocampal neurons and astrocytes. Synaptojanin 1, a brain enzyme that breaks down PIP2, was correspondingly elevated in brain tissues from mouse and human ApoE4 carriers.
When levels of the enzyme were genetically tamped down in ApoE4 mice, cognitive deficits previously observed in behavioral tests, including memory impairment, failure to recognize familiar objects, and abnormal fear conditioning, were reversed, suggesting that restoring normal PIP2 levels can ameliorate AD-associated cognitive dysfunction.
Thus, the inability of ApoE4 carriers to maintain normal brain PIP2levels might underlie their increased risk of sporadic AD. According to the authors, synaptojanin 1 might serve as a potential drug target for treating AD.