Article I from Nature:
Nature 1999 Jul 8;400(6740):173-7
Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.
Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P
Elan Pharmaceuticals, South San Francisco, California 94080, USA. dschenk@elanpharma.com
Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology of Alzheimer's disease (AD). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the predominant form found in the amyloid plaques of Alzheimer's disease. The PDAPP transgenic mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner. In the present study, transgenic animals were immunized with Abeta42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-beta deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of beta-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-beta may be effective in preventing and treating Alzheimer's disease.
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Article II from The New England Journal of Medicine -- November 25, 1999 -- Vol. 341, No. 22
Immunologic Treatment of Alzheimer's Disease
The recent report by Schenk et al. (1) raises the hope of a vaccine for Alzheimer's disease. This report has justifiably received wide attention in both the scientific and lay media. It describes an initial study in transgenic mice, which had been developed as an animal model to test potential treatments for Alzheimer's disease.
Scientifically, the paper is straightforward and impressive. The authors studied transgenic mice that overexpress a mutant form of the human amyloid precursor protein. The cerebral amyloidosis that develops in these animals is similar to that in the brains of patients with Alzheimer's disease. (1) Cerebral amyloidosis was largely prevented in animals that were immunized with a fragment of amyloid precursor protein (namely, A(beta)42) at the age of six weeks, before amyloid began to accumulate in their brains. Immunization of 11-month-old mice, after amyloid began to be deposited in the brain, reduced the amount of cerebral amyloidosis expected with aging, as evidenced by examination of their brains 7 months later. The transgenic animals might be expected to recognize the amino acid sequence of the protein as "self," because they carry the mutant human gene in their genome. Perhaps the protein fragment used for the immunization folds in such a way as to create an antigenic surface that the immune systems of the mice recognize as foreign.
Many workers in the field of Alzheimer's disease have accepted the idea that the deposition of dense amyloid is the critical event, with cerebral amyloidosis leading to the brain damage that causes the signs and symptoms of the disease. This train of events has been called the amyloid-cascade hypothesis of Alzheimer's disease. If this idea is correct and if immunization prevents the accumulation of amyloid in patients at risk for Alzheimer's disease or ameliorates amyloidosis in patients with established disease, then the report of Schenk et al. has many implications for the care of our aging population and for public health. The clinical implications are potentially so important that clinicians and scientists must be cautious in drawing conclusions from it.
First, there have not yet been any clinical studies of this technique in humans. Until such data become available, no definitive conclusions can be drawn about the clinical importance of these findings. Second, immunization with an abnormal (mutant) protein might lead to antibodies that react with the normal, endogenous protein that is expressed throughout the body in humans. Immunization was not reported to be harmful to the transgenic mice in which the protein was overexpressed. Amyloid precursor protein is, however, a nexin and appears to have a role in normal physiology. For example, one of the splice variants of the protein is found in high concentrations in platelets. Amyloid precursor protein-knockout mice have neurologic deficits. (2) Therefore, immunization of humans may not be harmless.
A third caveat pertains to the role of amyloid in causing brain damage in Alzheimer's disease and to the usefulness of transgenic mice that overexpress human mutant amyloid as models of human Alzheimer's disease. (3) In rapidly developing areas of science and medicine, the cutting edge of knowledge is often marked by controversy. Views on the validity of the amyloid-cascade hypothesis differ sharply among those who study Alzheimer's disease. Most investigators now probably focus on amyloid, but other mechanisms under study include cytoskeletal abnormalities, inflammation, oxidative stress, and other metabolic abnormalities. (3)
One of the strong arguments for the amyloid-cascade hypothesis is the close association of relatively rare, early-onset, familial forms of Alzheimer's disease with mutations in the gene encoding amyloid precursor protein or in genes encoding presenilin proteins, which affect the processing of amyloid precursor protein. One of the strong arguments against the hypothesis is that a large percentage (4) of older persons with intact cognition have enough amyloid in their brain at autopsy to fulfill the neuropathological criteria for Alzheimer's disease. These include a woman who died at the age of 102, who was intellectually sharp on detailed testing, and whose brain at autopsy showed severe cerebral amyloidosis and other histologic hallmarks characteristic of advanced Alzheimer's disease. (4)
The interpretation of other types of data relevant to the amyloid-cascade hypothesis is not clear-cut. The toxicity of fragments of amyloid precursor protein in vitro appears to be mediated by free radicals (reactive oxygen species). (5) This effect may be important in causing Alzheimer's disease. However, it may also be an artifact of the tendency of purified amyloid precursor protein and peptides derived from the protein to be auto-oxidized in air to forms containing free radicals.
Whether transgenic mice that express mutant amyloid precursor protein are good models for other types of brain damage associated with Alzheimer's disease is currently being debated. Specifically, there is controversy about whether the accumulation of amyloid in the brains of these mice leads to the loss of biologically significant numbers of neurons and to impairments in the ability to perform behavioral tasks that require memory. Schenk et al. (1) do not discuss whether reducing the amyloid burden in the brains of the transgenic mice improved their memory.
The immunologic approach may be a good way to test the validity of the amyloid-cascade hypothesis. If reducing cerebral amyloidosis mitigates the clinical manifestations of Alzheimer's disease in humans, the finding not only would be important in its own right, but also would prove that amyloid is critical in causing the disease. The finding that prevention of amyloidosis does not substantially ameliorate the clinical manifestations of Alzheimer's disease would argue strongly against the importance of amyloidosis in the pathophysiology of the disease.
The work of Schenk et al. (1) is elegant science that raises exciting possibilities for the prevention and treatment of Alzheimer's disease. Until more information becomes available, however, scientists and clinicians need to be guarded in their interpretations of its clinical importance.
John P. Blass, M.D., Ph.D.
Cornell University at Burke Medical Research Institute
White Plains, NY 10605 |
