P4‐252: Chronic treatment with an 11‐mer CNTF peptide rescues synaptic deficit and cognitive impairment in a rat model of sporadic Alzheimer's disease
Year: 2011
Type: article
Abstract: We previously reported (i) that inhibitor-2 (I2) of protein phosphatase-2A (PP2A) is cleaved into an N-terminal (I2NTF) and a C-terminal (I2CTF) fragment and translocated from neuronal nucleus to cytoplasm in Alzheimer disease (AD) brain (Tanimukai et al. 2005); and (ii) that the expression of I2CTF in brain results in neurodegeneration associated with tau and Abeta pathologies (Wang et al. 2010). In parallel, we showed that treatment of a 3xTg-AD transgenic mouse with Peptide 6, an 11-mer peptide corresponding to an active region of the ciliary neurotrophic factor (CNTF), can rescue neuroplastic deficit and cognitive impairment (Blanchard et al. 2010). The objectives of this study were to assess (i) the effect of brain expression of I2NTF and I2CTF on synaptic plasticity and cognitive performance in rats, and (ii) the rescue of neurodegeneration and cognitive deficit by Peptide 6. An adeno-associated virus serotype 1 (AAV1) was injected bilaterally in the brains of newborn rats to induce the expression of both I2NTF and I2CTF. Then 2.5 months later we treated AAV1-I2NTF-CTF infected rats and control littermates infected with the empty vector with Peptide 6 (10 nmol/25 g/day, i.p. injections) for 40 days. At the end of the treatment hippocampus-dependent learning and memory functions were behaviorally evaluated. Animals were then sacrificed and brains processed for immunohistochemical investigation of neuronal plasticity. We found that AAV1-I2NTF-CTF transduction significantly impaired both spatial reference and working memories and that treatment with Peptide 6 fully rescued cognition without inducing any side effects. AAV1-I2NTF-CTF infected rats also showed severe dendritic and synaptic loss as reflected by reduced expression of the microtubule associated protein MAP2 and the phosphoprotein synapsin 1. Peptide 6 treated rats showed a significant increase of dendritic and synaptic density, especially in the pyramidal neurons of CA1 and CA3 of the hippocampus. These findings suggest that expression of I2NTF and I2CTF provide a disease relevant non-transgenic model of sporadic AD. Peptide 6 can rescue behavioral impairment indicating that the increase of synaptic density is functionally effective in this animal model of AD.
Source: Alzheimer s & Dementia
Institution: Huazhong University of Science and Technology
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2027760504