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Presenilin Gene Mutation Linked to Familial form of Alzheimer's Disease

By LabMedica International staff writers
Posted on 24 Mar 2015
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Image: Comparing sections of cortex from a control mouse (left) to a mouse with a presenilin-1 mutation (right). The dashed line indicates the surface of the brain. Presenilin-1 mutations decrease gamma-secretase activity and cause features of neurodegeneration, including shrinkage of the cortex, as shown above (Photo courtesy of Dr. Raymond Kelleher and Dr. Jie Shen, Harvard Medical School).
Image: Comparing sections of cortex from a control mouse (left) to a mouse with a presenilin-1 mutation (right). The dashed line indicates the surface of the brain. Presenilin-1 mutations decrease gamma-secretase activity and cause features of neurodegeneration, including shrinkage of the cortex, as shown above (Photo courtesy of Dr. Raymond Kelleher and Dr. Jie Shen, Harvard Medical School).
Results obtained in studies using a genetically engineered mouse model of hereditary Alzheimer's disease pointed to the importance of reduced gamma-secretase activity caused by a mutation in the presenilin (PSEN1) gene.

Most cases of Alzheimer's disease are not hereditary. However, there is a small subset of cases that have an earlier age of onset and have a strong genetic element. In patients suffering from this form of Alzheimer's disease (autosomal dominant hereditary), mutations in the presenilin proteins (PSEN1 and PSEN2) or the amyloid precursor protein (APP) can be found. The majority of these cases carry mutant presenilin genes. An important factor in the disease process in AD is the accumulation of amyloid beta (Abeta) protein. To form Abeta, APP must be cut by two enzymes, beta-secretase and gamma-secretase. Presenilin is the sub-component of gamma-secretase that is responsible for the cutting of APP. Individuals with a hereditary form of AD over produce type 42 amyloid beta protein (Abeta42), which readily accumulates in the amyloid plaques that characterize the disease.

Investigators at Harvard Medical School (Boston, MA, USA) generated PSEN1 knockin (KI) mice carrying the familial Alzheimer’s disease (FAD) mutation L435F or C410Y.

They reported in the March 4, 2015, online edition of the journal Neuron that KI mice homozygous for either mutation recapitulated the phenotypes of mice that had been genetically engineered to completely lack PSEN1. Neither mutation altered PSEN1 mRNA expression, but both abolished gamma-secretase activity. Heterozygosity for the KI mutation decreased production of Abeta40 and Abeta42, increased the Abeta42/Abeta40 ratio, and increased Abeta deposition. In addition, the L435F mutation impaired hippocampal synaptic plasticity and memory and caused age-dependent neurodegeneration in the aging cerebral cortex. Collectively, the findings revealed that FAD mutations could cause complete loss of presenilin-1 function in vivo, suggesting that clinical PSEN mutations produce FAD through a loss-of-function mechanism.

"This is a very striking example where we have mutations that inactivate gamma-secretase function and yet they trigger an array of features that resemble Alzheimer's disease, notably synaptic and cognitive deficits as well as neurodegeneration," said senior author Dr. Raymond Kelleher, professor of neurology at Harvard Medical School. "This study is the first example of a mouse model in which a familial Alzheimer's mutation is sufficient to cause neurodegeneration. The new model provides an opportunity that we hope will help with the development of therapies focusing on the devastating neurodegenerative changes that occur in the disease."

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