P4‐224: Rescue of cognitive impairment and neuronal plasticity with a neurotrophic peptide in a rat model of sporadic Alzheimer's disease

Abstract

The hippocampus, which is the most affected in Alzheimer's disease (AD), is also a brain area where neurogenesis is known to take place throughout life. AD brain attempts to replace the lost with new neurons but the newborn cells, probably because of an unsuitable neurotrophic microenvironment, fail to mature into functional neurons (Li, B et al., J Neuropathol Exp Neurol 67:78-84, 2008). Additionally, AD is associated with a chronic progressive loss of neuronal plasticity in most of the cerebral cortex. Thus, one therapeutic approach to AD is the pharmacologic enhancement of neurogenesis and neuronal plasticity. A rat model of sporadic AD in which adeno associated virus vector is used to express N-terminal and C-terminal fragments of inhibitor-2 of protein phosphatase-2A, I 2NTF-CTF, and in which abnormal hyperphosphorylation and aggregation of tau and intraneuronal Ab are seen at ∼12 months, was used in this study (Bolognin et al., Acta Neuropathol 123:133-151, 2012). The 2-5 month AAV1-I 2NTF-CTF and, as a control, AAV1-GFP rats were treated with 400 nmoles/kg body weight of Peptide 6 or vehicle only (saline) daily injection for six weeks; Peptide 6 is a ciliary neurotrophic factor mimetic peptide that we previously showed to enhance neurogenesis and neuroplasticity, and improve cognition of normal adult mice (Chohan et al., Neurobiol. Aging 32:1420-1434, 2011), 3xTg-AD triple transgenic AD mice (Blanchard et al., Acta Neuropathol 120:605-621, 2010), and trisomic Ts65Dn Down mice (Blanchard et al., J Neuropathol Exp Neurol 70:1070-1079, 2011). Peripheral administration of Peptide 6 rescued cognitive impairment which was associated with increase in mRNA of brain derived neurotrophic factor and dentate gyrus neurogenesis. Moreover, the I 2NTF-CTF rats treated with Peptide 6 showed a significant increase in markers of neuronal plasticity. These studies suggest (i) a therapeutic potential of Peptide 6 and (ii) a proof of principle of treatment of AD by enhancing neuroregeneration.