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PubMedDate not supplied

Current concepts and future prospects for Alzheimer disease vaccines.

Alzheimer disease (AD) is the most prevalent form of dementia worldwide and is characterized by the progressive accumulation of the 42-residue amyloid beta protein (A beta) in brain regions serving memory and cognition. Only a few years ago, the proposition that AD may be amenable to any kind of therapy would have met with considerable skepticism. Yet, recent, exciting developments appear to suggest that immunizing against A beta may bear some potential for arresting or even curing AD. However, a clinical trial of vaccination with synthetic human A beta in AD patients was halted because of the development of meningoencephalitis in some patients. Further studies aimed at elucidating the mechanism of A beta clearance upon A beta immunization are needed. Such knowledge might facilitate the design of specific vaccination regimens, allowing exclusive targeting of A beta plaques without inducing detrimental side effects.

Alzheimer Disease↗
PubMedDate not supplied

Lessons from the AN 1792 Alzheimer vaccine: lest we forget.

Recent clinical and neuropathological data show that the AN 1792 vaccine enhanced the production of Abeta antibodies in the sera of Alzheimer's disease (AD) patients, but it appears to have been ineffective at stimulating the removal of Abeta deposits from the brain or at slowing the rate of cognitive decline. The 19 cases of meningoencephalitis were not linked in an obvious way to serum antibody titre, but they may have been linked to infiltration of the brain by antibodies and/or T-cells. Brain imaging indicated that oedema associated with the neuroinflammation did not reflect the typical distribution of neuritic plaques in AD. These outcomes were not anticipated by experiments on transgenic mice because compared to humans, these mice have less genetic variability, and their plaques have a different chemical composition, making them far more soluble and easier to remove. Furthermore, the consequences of vaccination are different. Vaccination of transgenic mice removes superfluous human Abeta while leaving endogenous mouse Abeta intact, whereas in humans the immune response is directed against an endogenous target that occurs naturally and is present in healthy brain tissue. The most important lesson to be learned from the AN 1792 trials is that new strategies for treating AD should not be tested on humans until they have been extensively tested on non-murine species.

Alzheimer Disease↗
PubMed2003

Alzheimer vaccine: amyloid-beta on trial.

A new therapeutic approach is being developed for the treatment of Alzheimer's disease (AD). This approach involves the deliberate induction of an autoimmune response to amyloid-beta (Abeta) peptide, the constituent of neuritic plaques that is thought to cause the neurodegeneration and dementia in AD. If this approach is to be effective, antibodies must be produced that can selectively target the toxic forms of Abeta, while leaving the functionally-relevant forms of Abeta and its precursor protein untouched. Furthermore, an approach needs to be found that avoids provoking an acute neuroinflammatory response. The situation is made even more challenging by uncertainty regarding which isoforms of Abeta contribute to the pathogenesis of AD.

Alzheimer Disease↗
PubMed2004

[Treatment of Alzheimer disease: A beta vaccine].

Alzheimer disease (AD) is regarded as an amyloidosis of the brain, and, therefore, the prevention/deletion of beta amyloid deposition is one of the most promising target of the treatment. Particularly, immune-mediated strategy is now known as A beta vaccination, which is thought to be a highly feasible way being applicable to AD patients. The A beta vaccination was originated by Schenk et al. in 1999. Since active and passive immunization of amyloid precursor protein (APP) gene- transgenic mice showed significant reduction of beta amyloid deposits in the brain and the immunized mice showed improvement in cognitive functions, clinical trials were performed in US and Europe. However, the trial was suspended, because about 6% of patients who received the vaccine developed meningoencephalitis probably mediated by T cells reactive to A beta. Although the trial was halted, an autopsy case who had had the meningoencephalitis suggested the disappearance of senile plaques (Nicoll et al., 2003). Moreover, patients who developed antibodies that recognize senile plaques by immunohistochemistry showed significantly milder decline of cognitive functions than those who did not (Hock et al., 2003). Here, we report a safe and effective oral vaccine using adeno-associated virus vector carrying A beta cDNA tested in tg2576 mice.

Alzheimer Disease↗
PubMed2005

New directions towards safer and effective vaccines for Alzheimer's disease.

The first experimental vaccine against Alzheimer's disease caused encephalitis in some patients, which led to termination of the clinical trial and dealt a serious blow to this therapeutic approach. With second-generation vaccines that are likely to circumvent this side effect, this type of therapy remains promising, although more extensive animal studies are likely to be required before approval of other clinical trials. Another potential side effect, microhemorrhages within the brain vasculature, has been observed in mouse models following passive immunization, but has not been assessed in reports of active vaccination. Together, these serious adverse reactions emphasize the need to test potential Alzheimer's immunotherapy in large cohorts of primate models prior to, or at least concurrently with, human trials, as no effective therapy exists for the disease.

Alzheimer Disease↗
PubMed2005

Induction of anti-inflammatory immune response by an adenovirus vector encoding 11 tandem repeats of Abeta1-6: toward safer and effective vaccines against Alzheimer's disease.

Induction of an immune response to amyloid beta-protein (Abeta) is effective in treating animal models of Alzheimer's disease. Human clinical trials of vaccination with synthetic Abeta (AN1792), however, were halted due to brain inflammation, presumably induced by T cell-mediated immune responses. We have developed an adenovirus vector as a "possibly safer" vaccine. Here, we show that an adenovirus vector encoding 11 tandem repeats of Abeta1-6 can induce an immune response against amyloid beta-protein. Much higher titers against amyloid beta-protein were observed when an adenovirus vector encoding GM-CSF was co-administered. Immunoglobulin isotyping revealed a predominant IgG1 response, indicating anti-inflammatory Th2 type. Immunohistochemical analysis revealed no inflammation-related pathology in the brain of mice immunized with the adenovirus vector. Induced antibodies strongly reacted with amyloid plaques in the brain, demonstrating functional activity of the antibodies. Thus, the adenovirus vector encoding 11 tandem repeats of Abeta1-6 may be a safer alterative to peptide-based vaccines.

Adenoviridae↗
PubMedDate not supplied

A safer vaccine for Alzheimer's disease?

Recent reports indicate that amyloid-beta (Abeta) vaccine-based therapy for Alzheimer's disease (AD) may be on the horizon. There are, however, concerns about the safety of this approach. Immunization with Abeta1-42 may not be appropriate in humans because it crosses the blood-brain barrier, can seed fibril formation, and is highly fibrillogenic. Abeta1-42 fibrils can in turn cause inflammation and neurotoxicity. This issue is of a particular concern in the elderly who often do not mount an adequate immune response to vaccines. Our findings show that vaccination with nonamyloidogenic/nontoxic Abeta derivative may be a safer therapeutic approach to impede the progression of Abeta-related histopathology in AD. Although the site of action of the anti-Abeta antibodies has been suggested to be within the brain, peripheral clearance of Abeta may have a greater role in reducing cerebral amyloid plaques in these animals and eventually in AD patients. Antibodies in general are predominantly found outside the central nervous system (CNS) and will, therefore, primarily clear systemic Abeta compared to brain Abeta. This disruption of the equilibrium between central and peripheral Abeta should then result in efflux of Abeta out of the brain, and subsequent removal of plaques. Abeta therapy can be targeted to the periphery, which may result in fewer CNS side effects, such as inflammation. Future Abeta derived vaccines should include T(h) epitopes, carriers and/or lipid moieties to enhance antibody production in the elderly, the population predominantly affected by AD.

Alzheimer Disease↗
PubMed2002

Alzheimer's vaccine: a cure as dangerous as the disease?

Studies in transgenic mouse models of Alzheimer's disease suggested the potential for a vaccine development. However, some patients in the human clinical trials developed symptoms of brain inflammation, demonstrating the high risk of a deliberately induced auto-immune response.

Adjuvants, Immunologic↗