Amyloid Vaccine for Alzheimer’s?
Abstract & Commentary
Source: Schenk D, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400:173-177.
Extraordinary findings by researchers at elan pharm-aceuticals suggest the possibility that immunization with beta-amyloid could be effective in treating and preventing Alzheimer’s disease. In an unprecedented approach, Schenk and colleagues studied the effects of injecting the 42-peptide form of human beta-amyloid protein into transgenic mice (PDAPP) that overexpress the human-mutant-amyloid-precursor protein (APP). These mice typically develop several features of Alzheimer-like pathology, including amyloid plaques, degenerating neurites, and astrogliosis within one year of birth. In initial experiments, amyloid injections were begun during the first six weeks of life and continued monthly until the mice were 1 year of age. Control PDAPP animals developed extensive amyloid deposits in multiple brain regions over this period. Mice injected with beta-amyloid had nearly complete absence of amyloid deposits in their brains and, likewise, they lacked dystrophic neurites and astrogliosis in most cases.
Schenk et al next evaluated whether immunization with beta-amyloid would affect neuropathological findings if initiated after a substantial burden of plaques already existed in the brain. In this case, they began injections at 11 months of age and continued for either four or seven months. Quantitative image analysis was used to measure alterations in amyloid burden relative to control animals receiving injections of a nonamyloid compound. The control mice exhibited a 17-fold increase in brain beta-amyloid burden from 12-18 months of age while beta-amyloid-injected animals had a 99% reduction in amyloid burden over a comparable period. Both diffuse and mature amyloid deposits were reduced in the beta-amyloid-immunized mice and remaining plaques often stained positive for IgG. The other elements of Alzheimer-like pathology present in this mouse model, such as neuritic dystrophy and astrogliosis, were also significantly reduced by beta-amyloid immunization.
In explaining their results, Schenk et al cite the considerable body of evidence indicating that a chronic inflammatory state exists in the brains of patients with Alzheimer’s disease, and suggest that augmenting the specific immune response to beta-amyloid may prove beneficial in preventing and treating the disorder in humans.
Although medical science usually moves forward in small, logical steps, major advances are occasionally wrought by conceptual leaps of faith. The very idea that generating a specific peripheral immune response would significantly alter Alzheimer’s neuropathology within the immunologically privileged confines of the blood-brain barrier seemed sufficiently far-fetched to deter most investigators from even considering this approach until now. Having obtained this fortunate outcome in young transgenic mice, Schenk et al pressed on to see what effect they might have on older animals with already established neuropathological changes. A reasonable expectation might have been that immunization would arrest subsequent plaque development without affecting existing deposits. Once again, expectations were violated as Schenk et al carefully documented a substantial reduction in both the total amyloid burden and other features of Alzheimer-like pathology. In total, these findings are so unexpected that their credibility almost certainly would have been doubted were they the work of less accomplished and respected scientists.
Many tantalizing questions remain to be addressed. The most pressing issues are whether a vaccine based on beta-amyloid could be safely used in humans and if this treatment will have the desired effect on the development and progression of Alzheimer’s disease. One safety concern relates to the constitutive expression of beta-amyloid throughout the body that could lead to an autoimmune response to a vaccine based on the human protein.
Accepting that these results will be replicated in other transgenic animal models, the applicability of these findings to the human disease remains in question. Overproduction of a mutant form of beta-amyloid is known to be pathologically relevant to a small number of early-onset familial cases of Alzheimer’s associated with possession of specific autosomal dominant mutations. Although several lines of evidence point to a central role for beta-amyloid in the more commonly occurring forms of Alzheimer’s disease, it is unclear whether interventions affecting amyloid clearance in PDAPP mice will prove applicable to human patients lacking this mutation. Furthermore, the PDAPP mice (indeed, all of the existing amyloid-based transgenic models) lack key elements of human Alzheimer’s pathology, particularly neurofibrillary tangles. In several other neurodegenerative disorders, tangles develop in the absence of senile plaques. This makes it conceivable that an intervention that prevents, or even reverses, amyloid deposition may still not cure the disease.
The only way to satisfactorily answer these questions is to test this approach in human patients. Before human trials can be initiated, technical issues concerning the appropriate choice of adjuvants and avoidance of autoimmune responses must be addressed. This approach is likely to be fast-tracked for human trials by both the pharmaceutical company and federal regulatory agencies in light of the far-reaching implications of these animal studies. Although it may be several years before safety and efficacy are established, many interesting neurobiological questions should be answered in the process of testing this extremely exciting and unexpected new inroad to Alzheimer’s therapy. —nrr
Injections of beta-amyloid into transgenic mice bearing Alzheimer-like pathology:
a. cause a fatal autoimmune response.
b. decrease amyloid burden but not other Alzheimer-like pathology.
c. decrease amyloid burden, astrogliosis, and neuritic dystrophy.
d. have no measurable effect on brain pathology.