Abstract

In addition to neurofibrillary tangles and Aβ plaques, the two histopathological hallmarks, neurogenesis and neuronal plasticity are markedly altered in Alzheimer's disease. While one therapeutic approach, toward which most of the current efforts in the field are being made, is to inhibit neurodegeneration, another is to shift the balance from neurodegeneration to neurogenesis and neuronal plasticity by employing the regenerative capacity of the brain. We have recently shown that an 11-mer peptide, Peptide 6, corresponding to an active region of CNTF, can enhance the dentate gyrus neurogenesis and neuronal plasticity (Chohan et al. 2009).To assess whether treatment with Peptide 6 can reverse cognitive impairment by enhancing neurogenesis and neuronal plasticity before the formation of Aβ plaques and neurofibrillary tangles in 3xTgAD mice. We administered peripherally Peptide 6 or vehicle control for six weeks (daily i.p. 50 nmol/injection) to 7-8 months 3xTgAD mice and WT control animals. At this age the transgenic mice were cognitively impaired but had no Aβ plaques or tangles. After four weeks of treatment, general behavior and learning and memory function were evaluated. At the end of behavioral studies, animals were sacrificed, and the effects of treatment with Peptide 6 on Aβ and tau pathologies and neurogenesis and neuronal plasticity were studied. Treatment with Peptide 6 did not induce weight loss or other side effects known to be caused by CNTF. Instead the Peptide 6 reversed impairments in object discrimination task as well as in spatial reference memory task in transgenic mice. While this treatment had no detectable effect on Aβ and tau pathologies, it enhanced neurogenesis in dentate gyrus, reduced ectopic birth in the granular cell layer, and increased neuronal plasticity in the hippocampus and in the cerebral cortex. These findings, for the first time, demonstrate that pharmacological enhancement of neurogenesis and neuronal plasticity can be sufficient to reverse cognitive impairment in transgenic mouse model of AD pathology.

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