Genetic Restoration Of Plasma ApoE Improves Learning & Memory In ApoE-Deficient Mice

Alzheimer's disease (AD) is the most common form of dementia in individuals over the age of 65 years. The most prevalent genetic risk factor for AD is the E4 allele of apolipoprotein E (ApoE4), and novel AD treatments that target ApoE are being considered. One proposed treatment strategy for Alzheimer's disease (AD) is the reduction of ApoE.

Researchers suggest that ApoE knock-out (KO) mice have synaptic loss and cognitive dysfunction; however, these findings are complicated by the fact that ApoE knock-out mice have highly elevated plasma lipid levels, which may independently affect brain function.

To bypass the effect of ApoE loss on plasma lipids, researchers generated a novel mouse model that expresses ApoE normally in peripheral tissues, but has severely reduced ApoE in the brain. This allows researchers to study brain ApoE loss in the context of a normal plasma lipid profile.

The results showed that the brain ApoE knock-out (bEKO) mice had synaptic loss and dysfunction similar to that of ApoE KO mice; however, the bEKO mice did not have the learning and memory impairment observed in ApoE KO mice.

Moreover, the memory deficit in the ApoE KO mice was specific to female mice and was fully rescued in female bEKO mice.

These findings suggest that plasma lipid levels can influence cognition and synaptic function independent of ApoE expression in the brain.

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A major concern of this strategy is that an animal model of ApoE deficiency, the ApoE knock-out (KO) mouse, has reduced synapses and cognitive impairment; however, these mice also develop dyslipidemia and severe atherosclerosis.

While this does not rescue synaptic loss, it does completely restore learning and memory in the mice, suggesting that both CNS and plasma ApoE are independent parameters that affect brain health.

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Source-Medindia