Public Release: 

Study Implicates Programmed Cell Death In Familial Alzheimer's Disease

NIH/National Institute of Allergy and Infectious Diseases

Scientists have found additional evidence that dysregulation of programmed cell death --the normal process by which old or superfluous cells self-destruct -- may underlie the earlier onset and more rapid downhill course of inherited forms of Alzheimer's disease.

As reported in the Dec. 6 issue of Science by scientists from the National Institutes of Health (NIH), Loyola University Medical Center in Maywood, Ill., and Harvard Medical School in Charlestown, Mass., the new findings may help explain the features that distinguish familial Alzheimer's disease, which clusters in families, from the more common, late-onset form of the disease. Luciano D'Adamio, M.D., Ph.D., chief of the T Cell and Molecular Biology Unit at the National Institute of Allergy and Infectious Diseases (NIAID), and Benjamin Wolozin, M.D., Ph.D., an Alzheimer's disease researcher formerly with the National Institute of Mental Health (NIMH) and now at Loyola, led the collaborative research study.

Alzheimer's disease is the single greatest cause of mental impairment in older people, affecting an estimated 4 million people in the United States. Familial Alzheimer's disease accounts for up to 10 percent of all cases. Recently it has been linked to the inheritance of specific mutations in any of three genes: presinilin-1 (PS1), PS2 and amyloid precursor protein (APP). An extremely aggressive form of the illness, familial Alzheimer's disease strikes people between ages 30 and 60 and progresses much more quickly than sporadic Alzheimer's disease, which generally develops after age 65. Otherwise, however, the two types of the illness -- which strips away memories and leads to mental confusion -- are indistinguishable, characterized by the loss of neurons and the development of amyloid plaques and neurofibrillary tangles in the brain.

The new report extends the findings that the three NIAID co-authors published earlier this year in Science. In the course of investigating several genes they had identified as being involved in apoptosis, or programmed cell death -- the choreographed cell suicide that helps sculpt developing tissues and organs -- they stumbled across a gene fragment that is a piece of mouse PS2. It was the first objective evidence that part of the programmed cell death pathway might be involved in Alzheimer's disease.

In the current paper, the authors report the results of a series of experiments conducted with model neuronal cells to study PS2 function, to determine how the mutant PS2 found in familial Alzheimer's patients affects the role of PS2 in apoptosis. They also examined if PS2 might play a role in apoptosis induced by a mutant APP. APP gives rise to beta-amyloid peptide, which is toxic to cells and collects in the plaques found in Alzheimer brains. Finally, they investigated whether PS2 and APP -- which are transmembrane proteins, meaning each contains domains that cross the cell membrane -- might act via signalling through certain kinds of so-called G proteins, proteins lodged in the cell membrane that bind molecules involved in energy transfer.

"I think we have established pretty convincingly that PS2 is required for some form of apoptosis in different cell types," comments Dr. D'Adamio. "In the system we have studied, it is clear that mutation exacerbates this function." The results of their experiments demonstrate that:
1) PS2 is not only required for T-cell receptor triggered cell death (the finding of their earlier Science paper), but also for neuronal cell death;
2) a PS2 mutant associated with familial Alzheimer's disease causes much more apoptotic activity than does normal PS2;
3) PS2-mediated apopotosis can be blocked by pertussis toxin, an inhibitor of G proteins, suggesting that G proteins are required for PS2's function;
4) APP and PS2 share the same membrane signalling pathway; and
5) PS2 dramatically increases the susceptibility of cells to apoptosis induced by beta amyloid peptide, without affecting the level of APP.

Although they only experimented with PS2 and APP, they speculate that since PS1 is very similar to PS2, it could involve the same pathway.

The authors conclude, that the "activation of PS2 increases the susceptibility of neurons to apoptotic stimuli that could sensitize neurons to the harmful insults of aging, such as free radical-mediated oxidation and neurotoxicity resulting from aggregated beta-amyloid peptide. The accelerated rate of neuronal cell death that occurs in the brains of Alzheimer's patients may therefore result from the additive effects of activated apoptosis, aging and beta-amyloid peptide activity."

Furthermore, they note that activating PS2 also may indirectly contribute to the process of neurodegeneration by triggering a stress response that increases production of beta-amyloid peptide, as the authors note, "adding to the toxic burden in the brains of Alzheimer's patients and further accelerating the process of neurodegeneration."

Besides NIAID and NIMH, other NIH components involved in the study include the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the Public Health Service, U.S. Department of Health and Human Services.


Wolozin B, Iwasaki K, Vito P, Ganjei K, Lacaná E, Sunderland T, Zhao B, Kusiak JW, Wasco W, and D'Adamio L. PS2 participates in cellular apoptosis: constitutive activity conferred by Alzheimer mutation. Science 1996;274: 1710-13.

Vito P, Lacaná E, and D'Adamio L. Interfering with apoptosis: Ca2+2+ -binding protein ALG-2 and Alzheimer's disease gene ALG-3. Science 1996;271:521-15.

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