Therapies that reduce deposits of amyloid-β (Aβ) in the brain are ineffective at repairing neuronal impairment in mice and actually increase it, finds a study published online in Nature Neuroscience. Aβ deposits aggregate into clumps in the brain which are a pathological hallmark of Alzheimer's disease.
Expression of mutant human amyloid protein in animals results in deposits of Aβ plaques that induce abnormal increases in neuronal activity and impair the normal function of neuronal circuits.
Arthur Konnerth, Marc Busche and colleagues explored whether they could reverse these impairments by treating mice that overexpress the human mutant amyloid precursor protein with either of two different antibodies targeting Aβ (14 mice) or a control antibody (19 mice). They found that, although treatment with the Aβ targeting antibodies reduced the amount of plaques in the animals' brains, it also increased the amount of hyperactive neurons.
This was true whether the treatment was given to older mice (14 treated, 19 control) or younger mice in which the accumulation of Aβ had yet to occur (10 treated, 13 control). The same therapies had no effect on neuronal activity in a group of normal mice (5 treated, 3 control), suggesting that the observed exacerbation in mutant mice is dependent on the presence of Aβ and cannot be explained by incidental effects of inflammation in response to the antibodies.
The authors note that, although other research has shown that anti-Aβ treatment can prevent the weakening of neuronal connections and memory impairments in animal models of Alzheimer's disease, these benefits are not enough to repair neuronal dysfunction.
They suggest that their findings provide a cellular mechanism that may explain, in part, why treatments targeting Aβ in human clinical trials have failed to improve cognitive deficits. However, the authors point out that future studies are needed to determine whether the increase in abnormal neural activity seen in their animal models is related to the poor efficacy of Aβ therapy in patients.
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