Mechanism Behind Familial Alzheimer's is Different Than Thought

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Researchers from Massachusetts General Hospital and Brigham and Women’s Hospital in Boston found that mutations that trigger hallmark features of Alzheimer’s disease function by decreasing, not increasing function of the presenilin-1 protein and gamma-secretase enzyme.

The finding explains why drugs designed to block presenilin activity have failed, they reported in Neuron. The discovery sheds more light on rare cases of familial Alzheimer’s disease (FAD), which only accounts for about 1% of cases.

Mutations in presenilin genes accounts for about 90% of familial Alzheimer’s cases, and can cause symptoms to appear earlier than in cases with mutations in amyloid precursor proteins. The presenilin genes encode essential components of gamma secratase, which process amyloid precursor protein.

The researchers tested their hypothesis in a mouse model, in which specific FAD presenilin-1 mutations were “knocked in” to the gene, resulting in a similar gene expression as observed in humans. Mice that had two mutated copies of the gene did not survive, however mice with a single presenilin-1 gene mutation survived but had difficulties with learning and memory. Although production of beta-amyloid was reduced in the brains of these mice, there was proportionally more plaque-associated beta-amlyoid 42 generated. Upon examination, the brains of the mice showed similar synaptic dysfunction and age-related neurodegeneration as observed in Alzheimer’s patients.

"This paper clearly shows that these FAD mutations cause a loss of presenilin function and gamma secretase activity, leading to the loss of neurons in the adult brain," said Jie Shen, PhD, co-author of the study, in a press release. "The most important implication of our findings is that strategies that enhance rather than inhibit gamma secretase should be investigated as potential Alzheimer's therapies.” 

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Mechanism Behind Familial Alzheimer's is Different Than Thought

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.

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