Alzheimer Immunotherapy Wins by a Nose
Abstract & Commentary
Source: Weiner HL, et al. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease. Ann Neurol 2000;48:567-579.
Amyloid-based immunotherapy is currently under study as a potential treatment for Alzheimer’s Disease (AD). Phase I human trials were initiated in the United States soon after Schenk and colleagues in San Francisco demonstrated that repeated parenteral injections of the amyloid-beta (Ab) peptide dramatically reduced plaque-related pathology in a transgenic mouse model of AD (Schenk D, et al. Nature 1999; 400:173-177). A new study from Weiner and colleagues at Harvard replicates these findings, and demonstrates for the first time that intranasal administration of Ab peptide can also result in reduced plaque formation in transgenic mice.
The approach used by Weiner et al differs in several important respects from that used by the Schenk et al in their earlier work. Although both teams used the PDAPP transgenic mouse model, Weiner et al initiated amyloid administration later (5 months vs Schenk et al’s 6 weeks), and continued treatments for a shorter duration (7 months vs Schenk et al’s 11 months). They used the 40 peptide form of Ab in an unadulterated form, while Schenk et al used Ab-42 mixed with modified Fruend’s adjuvant. In the new study, mice were treated orally or intranasally with either low or high-dose amyloid peptide, and control animals were given myelin basic protein. Schenk et al used the parenteral administration only and had a more extensive set of controls. In both studies, a combination of immunohistochemistry and ELISA techniques were used to quantitate the effects of the immunotherapy on the Alzheimer-like pathology in various regions of the mice brains.
High-dose (25 mcg) Ab-40 introduced intranasally was associated with a 60% reduction in cerebral amyloid burden. High-dose oral Ab-40, low doses of intranasal Ab-40, and all doses of myelin basic protein did not alter amyloid accumulation significantly. The high-dose intranasal treatment also reduced microglial and astrocytic activation in the hippocampus, and led to the accumulation of small numbers of mononuclear cells in the brain. These changes were smaller in magnitude but otherwise closely paralleled the previously reported effects of parenteral injections of Ab-42, confirming the plaque-reducing potential of amyloid immunotherapy in this transgenic animal model of human AD.
Commentary
This study is the first to replicate the finding that central amyloid burden can be reduced by a peripheral immune response to the amyloid peptide in a transgenic animal model of AD. It also provides new evidence that cell-mediated immune mechanisms may play a role in mediating this phenomenon. Although the magnitude of the attenuation of plaque pathology achieved with intranasal administration was less than previously reported with parenteral injections, a more optimal response might be expected with a more sustained or intense course of treatment. Intranasal administration avoids the use of potentially harmful adjuvants and may prove more palatable to patients than parenteral injections. Weiner et al also suggest that nasal and parenteral routes of administration might be used adjunctively to further boost immune response. Whatever route of administration proves optimal, this study adds to a growing body of evidence that amyloid-based immunotherapy is a viable approach to test in AD treatment and prevention trials. —Norman R. Relkin
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