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New Research Explains How Genetic Changes Lead To Familial Alzheimer’s disease

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Mutations in the presenilin-1 gene are the very frequent cause of inherited, early-onset types of Alzheimer’s disease. In a new research, presented in Neuron, researchers substituted the normal mouse presenilin-1 gene with Alzheimer’s-causing forms of the human gene to find out how these genetic modifications may cause the disorder. Their surprising outcomes may transform the way researchers design medicines that target these mutations to deal with inherited or familial Alzheimer’s, a unusual form of the disease that impacts nearly 1% of individuals with the disorder. The research was partly funded by the National Institute of Neurological Disorders and Stroke (NINDS).

This image compares areas of cortex from a control mouse (left) to a mouse with a presenilin-1 mutation (right). The black line shows the surface of the brain. Presenilin-1 mutations reduce gamma-secretase activity and lead to features of neurodegeneration, such as shrinkage of the cortex, as displayed above. Image credit: Raymond Kelleher and Jie Shen
This image compares areas of cortex from a control mouse (left) to a mouse with a presenilin-1 mutation (right). The black line shows the surface of the brain. Presenilin-1 mutations reduce gamma-secretase activity and lead to features of neurodegeneration, such as shrinkage of the cortex, as displayed above. Image credit: Raymond Kelleher and Jie Shen

For many years, it has been not clear exactly how the presenilin mutations lead to Alzheimer’s disease. Presenilin is a element of an essential enzyme, gamma secretase, which cuts up amyloid precursor protein into two protein parts, Abeta40 and Abeta42.  Abeta42 is identified in plaques, the irregular accumulations of protein in the brain which are a trademark of Alzheimer’s. Several research recommended that presenilin-1 mutations enhanced activity of gamma-secretase. Researchers have designed drugs that stop gamma-secretase, but they have so far unsuccessful in clinical studies to stop the disease.

The research led by Raymond Kelleher, M.D., Ph.D. and Jie Shen, Ph.D., offers a plot twist in the connection of presenilin-1 mutations and inherited Alzheimer’s disease. Using mice with modified types of the presenilin gene, Drs. Kelleher and Shen identified that the mutations may lead to the disease by reducing, rather than increasing, the activity of gamma-secretase.

One of the presenilin mutations also triggered impairment of memory circuits in the mouse brain and age-dependent death of neurons.

Roderick Corriveau, program director at NINDS stated

“The results by Drs. Shen and Kelleher are a important departure from conventional thinking that must open up interesting and creative new opportunities at all levels of study, from basic molecular mechanisms all the way to clinical intervention.”

“This is a extremely stunning example where we have mutations that inactivate gamma-secretase function and yet they induce an array of features that resemble Alzheimer’s disease, especially synaptic and cognitive deficits along with neurodegeneration,” stated Dr. Kelleher.

Even though plaques are the primary biological indicator of Alzheimer’s, neurodegenerative modifications are also an essential function of the disease. These modifications consist of loss of brain cells, cognitive deficits such as issues with memory, modifications in the brain’s electrical activity and inflammation. Generally used mouse models of the disease exhibit extreme plaque deposition, but never show symptoms of neurodegeneration. With respect to Dr. Kelleher, this may be one reason that therapies developed in mice have not been effective in patients.

“This research is the initial example of a mouse model in which a familial Alzheimer’s mutation is enough to lead to neurodegeneration. The new model offers a possibility that we wish will help with the advancement of therapies concentrating on the devastating neurodegenerative modifications that take place in the disease,” Dr. Kelleher said.

Dr. Shen’s past work confirmed that presenilins and gamma-secretase perform an essential function in learning and memory, communication between brain cells and neuronal survival, and cautioned towards the use of gamma-secretase inhibitors for Alzheimer’s disease treatment. Later, a huge phase III trial was ceased because therapy with a gamma-secretase inhibitor worsened the cognitive capability of patients.

Even though the greater part of cases are not inherited, familial Alzheimer’s disease is connected with early onset of the disorder, with symptoms usually appearing prior to age 60. Drs. Shen and Kelleher wish that the mechanisms discovered in this research may offer insight into the common forms of the disorder that impact more than 5 million people in the United States.

The outcomes in this paper recommend a new method for drug development. “We think that restoring gamma-secretase will be a better, more effective therapeutic approach for Alzheimer’s sufferers,” said Dr. Shen.