Harvard University. US: Study reveals new mechanism behind most common form of inherited Alzheimer’s disease. A study from Harvard Medical School researchers at Massachusetts
General Hospital and Brigham and Women’s Hospital 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 the March 4 issue of 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,” said Raymond J. Kelleher III, HMS assistant professor of neurology at Mass General and 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 is very rare,
accounting for only around 1 percent of cases, the identification more
than 20 years ago of the genes that cause familial Alzheimer’s disease
provided the first clues into the mechanism behind the effects of the
disease. The rarest familial Alzheimer’s disease-associated mutations
are found in the amyloid precursor protein, which is clipped by multiple
proteases to produce the beta-amyloid peptides that form the amyloid
plaques characteristic of the disease.
Mutations in two presenilin genes account for around 90 percent of
familial Alzheimer’s disease cases. These two genes encode essential
components of gamma secretase, one of the proteases that process amyloid
precursor protein. Individuals with presenilin-associated familial
Alzheimer’s disease develop Alzheimer’s symptoms even earlier than do
those with amyloid precursor protein 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, HMS professor of neurology at Brigham and Women’s and co-senior author of the Neuron
paper, questioned this widely held view and the use of gamma secretase
inhibitors to treat Alzheimer’s disease. 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
studies in which the overproduction of beta-amyloid or presenilins
failed to produce neurodegeneration.
In a 2007 paper published in PNAS, Shen and Kelleher—who had
been treating familial Alzheimer’s disease patients with mutations in
the presenilin-1 gene and researching brain mechanisms underlying
cognitive function—proposed what they termed the presenilin hypothesis: a
loss of presenilin function may be the primary event triggering
neurodegeneration and dementia in familial Alzheimer’s disease.
In recent studies, Kelleher identified a novel familial Alzheimer’s
disease-causing presenilin-1 mutation that inactivated its function in a
sensitive cell-culture system. In collaboration with Shen, his group
went on to show that a series of familial Alzheimer’s disease mutations
all impaired presenilin-1 function in cell culture.
These findings raised the pivotal question of how such mutations
affected presenilin-1 function in living animals, especially in the
brain. While Shen’s earlier investigations had used strains of mice in
which one or more copies of the presenilin genes were totally
inactivated, for this study she and Kelleher generated mice in which
specific, familial Alzheimer’s disease-associated presenilin-1 mutations
were “knocked in” to the gene, causing them to be expressed just as
they are in human patients with that particular mutation.
One of the mutations they tested is relatively common among familial
Alzheimer’s disease patients, while the other is fairly rare. Both are
located near the site where the protein interacts with its target
molecules when incorporated into gamma secretase. As was the case with
animals in which both copies of presenilin-1 were deleted in earlier
studies, those in which both copies were mutated did not survive after
birth. Mice in which a single presenilin-1 gene was mutated survived,
but they showed deficiencies in learning and memory compared with
control mice.
Production of beta-amyloid within the brains of these mice was
actually reduced, although the ratio between forms of the peptide was
changed, with proportionally more plaque-associated beta-amyloid 42
being generated. Closer examination of the brains of mice with the
familial Alzheimer’s disease mutation showed the same sort of synaptic
dysfunction and age-associated neurodegeneration seen in the brains of
patients with Alzheimer’s disease.
“This paper clearly shows that these familial Alzheimer’s disease
mutations cause a loss of presenilin function and gamma secretase
activity, leading to the loss of neurons in the adult brain,” said Shen.
“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. They also may explain why a major
clinical trial of a gamma secretase inhibitor failed to help patients
and actually worsened their cognitive abilities.”
Shen added that their presenilin hypothesis does not rule out a role
for beta-amyloid in Alzheimer’s pathology; it just places
presenilin/gamma secretase activity closer to the pathway that leads to
neurodegeneration.
While this study examined only presenilin-1 mutations, Kelleher noted
that the researchers believe that loss of function is a general
property of familial Alzheimer’s disease mutations in both presenilin
genes. Investigation of the mechanisms underlying the effects of the
amyloid precursor protein mutations is also warranted, as is examination
of how presenilin dysfunction may contribute to the common, late-onset
form of Alzheimer’s disease.
“Shared or convergent molecular pathways may be responsible for
pathogenesis in both familial and sporadic forms, and we hope that
mechanistic relationships will become clearer with the identification of
genetic risk factors for sporadic or late-onset Alzheimer’s disease,”
he said. “We’re now actively pursuing strategies to develop candidate
therapies that restore presenilin-1 function. We also hope that our
knock-in mouse model will facilitate development and preclinical testing
of these and other agents that can combat neurodegeneration in
Alzheimer’s disease.”
Adapted from a Mass General and Brigham and Women’s joint news release.