Apolipoprotein E2 May Act as a Protective Shield in Alzheimer’s

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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In a new study entitled “Human ApoE Isoforms Differentially Modulate Glucose and Amyloid Metabolic Pathways in Female Brain: Evidence of the Mechanism of Neuroprotection by ApoE2 and Implications for Alzheimer’s Disease Prevention and Early Intervention” researchers reported a breakthrough discovery when they showed ApoE2 human protein is a protective shield against Alzheimer’s disease, enhancing brain glucose metabolism and amyloid protein homeostasis. The study was published in the Journal of Alzheimer’s Disease.

Alzheimer’s disease is a devastating condition that progressively destroys memory and thinking skills. Currently affecting more than 5.1 million Americans, estimates point that in the future this number will triplicate. Without any cure in the horizon, despite over 100 human trials already performed, Alzheimer’s research continues in search of an effective treatment, as Liqin Zhao, assistant professor of pharmacology and toxicology at the University of Kansas School of Pharmacy noted, “There is no cure for Alzheimer’s disease. Five available Alzheimer’s disease drugs were all approved by FDA 10 years ago, and they provide only temporary symptomatic relief for an average of six to 12 months.”

Now, Dr. Zhao’s team has discovered that a protein called ApoE2, one of three existent types of ApoE proteins (Apolipoprotein E), has a protective role in Alzheimer’s disease. Far from new, several studies have focused on the role of ApoE proteins’ isoforms – ApoE2, ApoE3 and ApoE4 – but considerably fewer studies have focused on ApoE2. Moreover, its role in Alzheimer’s has remained poorly understood as Dr. Zhao noted, “Human ApoE is polymorphic and exists in three major alleles — ApoE2, ApoE3 and ApoE4. ApoE2 is a rare form and is considered neuroprotective. ApoE3 is the most common form and considered to play a neutral role in AD. ApoE4 is the greatest genetic risk factor for late-onset sporadic AD — ApoE4 occurs in only about 20 percent of the total population but accounts for approximately 50 percent of the Alzheimer’s disease population.”

Working with middle-aged female mice, the team discovered that human ApoE isoforms differentially modulate glucose and amyloid metabolic pathways, two key mechanisms that are significantly perturbed in mouse models of Alzheimer’s disease. Specifically, they discovered that among the three isoforms, ApoE2 was the strongest regulator of these metabolic pathways.

The team highlights that their findings show ApoE2 can enhance both energy production and amyloid homeostasis. As such, potentiating ApoE2 phenotypes in the brain may become a successful therapeutic strategy in Alzheimer’s disease, as Dr. Zhao noted, “This study essentially opens up a new line of research for us. We’re currently expanding our investigations to further test our hypothesis that bioenergetic robustness could serve as a major mechanism whereby ApoE2 delegates neuroprotection. If our hypothesis proves true, we can move forward with the idea that a strategy that enhances brain energy metabolism holds great promise for prevention, risk reduction or delaying the onset in an aging brain — in particular an ApoE4 brain — of Alzheimer’s disease.”