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Study reveals mechanism behind most common form of inherited Alzheimer’s disease

A study from researchers at Massachusetts General Hospital (MGH) and Brigham and Women’s Hospital (BWH) reveals for the first time exactly how mutations associated with the most common form of inherited Alzheimer’s disease produce the disorder’s devastating effects. Appearing in Neuron, the paper upends conventional thinking about the effects of Alzheimer’s-associated mutations in the presenilin genes and provides an explanation for the failure of drugs designed to block presenilin activity.

“Our study provides new insights into Alzheimer’s disease by showing how human mutations that cause the disease lead to neurodegeneration and dementia,” says Raymond J. Kelleher III, MD, PhD, of the MGH Department of Neurology and Center for Human Genetic Research, co-senior author of the Neuron paper. “We found that mutations in the presenilin-1 gene promote the hallmark features of the disease by decreasing, rather than increasing, function of the presenilin-1 protein and the gamma-secretase enzyme. In addition to the important therapeutic implications of our findings, we have also generated the first animal model in which an Alzheimer’s-disease-causing mutation produces neurodegeneration in the cerebral cortex.”

While inherited or familial Alzheimer’s disease (FAD) is very rare, accounting for only around 1 percent of cases, the identification more than 20 years ago of the genes that cause FAD provided the first clues into the mechanism behind the effects of the disease. The rarest FAD-associated mutations are found in the amyloid precursor protein (APP), which is clipped by multiple proteases to produce the beta-amyloid peptides that accumulate into the amyloid plaques characteristic of the disease. Mutations in two presenilin genes – which encode essential components of gamma secretase, one of the proteases that process APP – account for around 90 percent of FAD cases. Individuals with presenilin-associated FAD develop Alzheimer’s symptoms even earlier than do those with APP mutations.

While the mechanism by which presenilin mutations cause neurodegeneration has not been known, the general thinking was that they increase presenilin and gamma secretase activity, resulting in overproduction of beta-amyloid and particularly of beta-amyloid 42, which is thought to be more prone to deposition in plaques. As a result, development of gamma secretase inhibitors has been a major therapeutic effort pursued by pharmaceutical companies. But Jie Shen, PhD, of the Ann Romney Center for Neurologic Diseases at BWH, co-senior author of the Neuron paper, questioned this widely held view and the use of gamma secretase inhibitors to treat of Alzheimer’s disease because her earlier investigations into the normal function of the presenilin genes showed that genetically suppressing presenilin and gamma secretase activity in adult mice caused Alzheimer’s-like neurodegeneration, results that contrasted with those of studies in which the overproduction of beta-amyloid or presenilins failed to produce neurodegeneration.