Commentary Research Highlights (Amyloid and Alzheimer's Disease: Easing the Load)

Stephen D. Skaper

doi:10.2174/187152712799960745

Abstract

Alzheimer's disease (AD) is the principal cause of dementia, which is characterized by gradual onset of and progression of deficits in cognition and memory. The neuropathological hallmarks of AD are β-amyloid (Aβ) deposition in senile plaques and neurofibrillary tangles composed of the protein tau in a hyperphosphorylated state. The amyloid cascade hypothesis, which posits that deposition of Aβ in the brain parenchyma initiates a sequence of events that ultimately lead to AD dementia, has dominated research for the past twenty years. Drug development efforts have focused on reducing production of Aβ or enhancing its clearance from the brain. However, all of the Aβ-centric approaches that reached Phase III clinical trials have failed. These therapeutics were designed to decrease Aβ production (e.g. β- and γ- secretase inhibitors, γ-secretase modulators), to inhibit aggregation and/or bust plaques to improve Aβ clearance, and to inactivate Aβ through immunotherapy by active vaccination against the peptide or passive immunization with anti-Aβ antibodies. However, only direct intracranial delivery of anti-Aβ antibody â € “ a route of administration unlikely to be used in a clinical setting - has been definitively shown to clear preexisting deposits.

In a new study reported in The Journal of Neuroscience, Wang and colleagues evaluated the possibility of combining multiple anti-Aβ therapies in the treatment of AD. The authors used tet-off amyloid precursor protein (APP) transgenic mice combined with anti-Aβ immunotherapy. Treatment of amyloid-bearing tet-off APP mice with doxycycline was performed to suppress transgenic Aβ production before initiating a 12-week course of passive immunization. This strategy led to the preferential clearance of small deposits and diffuse Aβ surrounding fibrillar cores. Peripherally administered anti-Aβ antibody crossed the blood-brain barrier, bound to plaques, and was still found associated with a subset of amyloid deposits many months after the final injection. Antibody accessed the brain and enhanced microglial internalization of aggregated Aβ. To demonstrate the effectiveness of their approach in aged (18-24 month) animals, the authors suppressed transgenic APP until the mice reached 12 months of age, thus generating 18-month-old mice that carried only 6 months of amyloid load (thereby avoiding severe plaque burden before mid-life.). Combination therapy was equally effective in aged animals and in young (6-12 month) adults.

Repeated injections with anti-Aβ antibodies can increase vascular amyloid and microhemorrhage. However, the frequency of microhemorrhage but not the severity of individual bleeds was significantly increased by antibody treatment in the study by Wang et al. In addition, the authors did not directly test the effect of Aβ antibody alone in their tet-off APP mice. However, in an earlier study from this lab passive immunization using the same antibody found only modest attenuation of amyloid loads in APP transgenic mice that started antibody treatment with much less amyloid than the tet-off APP mice.

These caveats notwithstanding, the findings highlight a therapeutic potential for arresting the production of Aβ, with a combination therapy that allows microglial clearance to work from a static amyloid burden towards a significant reduction in plaque load. To paraphrase the authors: “draining a flood is easier once the water stops’.

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