From a drug perspective, it would not be an exaggeration to say that therapies developed to treat Alzheimer’s disease (AD) have fallen short. Yet thankfully, due to the perseverance of neuroscience researchers, there is no shortage of potential drug targets aimed at slowing the progression or even preventing AD. For instance, apolipoprotein E (apoeE) is a major genetic risk factor for the development of Alzheimer’s disease. However, this protein tends to be understudied as a potential druggable target for the mind-robbing neurodegenerative disease.

Now, a team of investigators, led by researchers at the University of South Florida Health (USF Health) reports that a novel apoE antagonist blocks apoE interaction with N-terminal amyloid precursor protein (APP). Findings from the new study were published recently in Biological Psychiatry through an article titled “A Novel Apolipoprotein E Antagonist Functionally Blocks Apolipoprotein E Interaction With N-terminal Amyloid Precursor Protein, Reduces β-Amyloid-Associated Pathology, and Improves Cognition.”

Interestingly, this peptide antagonist, known as 6KApoEp, was shown to reduce Alzheimer’s-associated beta-amyloid (β-amyloid) accumulation and tau pathologies in the brain, as well as improving learning and memory in mice genetically engineered to mimic symptoms of Alzheimer’s disease.

“For the first time, we have direct evidence that the N-terminal section of apoE itself acts as an essential molecule (ligand) to promote the binding of apoeE to the N-terminal region of APP outside the nerve cell,” explained lead study investigator Darrell Sawmiller, PhD, an assistant professor in the USF Health department of psychiatry & behavioral neurosciences. “This receptor-mediated mechanism plays a role in the development of Alzheimer’s disease. Overstimulation of APP by apoE may be an earlier, upstream event that signals other neurodegenerative processes contributing to the amyloid cascade.”

Many failed anti-amyloid therapies for AD have been directed against various forms of the protein β-amyloid, which ultimately forms clumps of sticky plaques in the brain. The presence of these amyloid plaques is one of the major hallmarks of AD.

The USF Health research findings suggest that disrupting apoE physical interaction with the N-terminal APP may be a new disease-modifying therapeutic strategy for this most common type of dementia.

“We investigated the binding of apoE, a peptide corresponding to its low-density lipoprotein receptor (LDRL) binding domain (aa 133-152, ApoEp) and modified ApoEp to amyloid precursor protein (APP) and their effects on Aβ production in cultured cells,” the authors wrote. “ApoE and ApoEp, but not truncated apoE lacking the LDLR binding domain, physically interacted with N-terminal APP and thereby mediated Aβ production. Interestingly, the addition of six lysine residues to the N-terminal ApoEp (6KApoEp) directly inhibited apoE binding to N-terminal APP and markedly limited apoE- and ApoEp-mediated Aβ generation, presumably through decreasing APP cellular membrane trafficking and p44/42 mitogen-activated protein kinase phosphorylation.”

Alzheimer’s disease is a global epidemic, afflicting an estimated 50 million people worldwide and 5.8 million in the United States, according to the Alzheimer’s Association. With the aging of the Baby Boomer generation, the prevalence of the debilitating disease is expected to increase dramatically in the coming years. Currently, no treatments exist to prevent, reverse, or halt the progression of Alzheimer’s disease, and current medications may only relieve dementia symptoms for a short time.

“Initially we wanted to better understand how apoE pathologically interacts with APP, which leads to the formation of β-amyloid plaques and neuronal loss,” concluded senior study investigator Jun Tan, PhD, MD, a professor in the USF Health department of psychiatry & behavioral neurosciences. “Our work further discovered an apoE derivative that can modulate structural and functional neuropathology in Alzheimer’s disease mouse models.”

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