P2‐219: Restorative effects of BDNF gene delivery into entorhinal cortex in APP transgenic mice
Year: 2009
Type: article
Abstract: Profound neuronal dysfunction and synapse loss in the entorhinal cortex and hippocampus lead to early impairment of short-term memory in Alzheimer's disease (AD). The growth factor Brain-Derived Neurotrophic Factor (BDNF) is normally expressed in the entorhinal cortex and hippocampus, modulates synaptic plasticity and cell survival, and exhibits declining levels in AD. Objectives: We tested the hypothesis that BDNF lentiviral gene delivery to the entorhinal cortex would improve behavioral, cellular and molecular abnormalities in a mouse genetic model of AD. APP transgenic mice (J20) bearing the Indiana (717V→F) and Swedish (671KM→NL) amyloid precursor protein (APP) mutations underwent injections of lentiviral vectors expressing either human BDNF or the reporter gene GFP at age 6 months, after disease onset. One month later, hippocampal-dependent learning and memory were tested in the Morris water maze and a contextual fear-conditioning paradigm. Brains were then removed and subjected to Affymetrix gene array studies and immunocytochemistry. We find that BDNF gene delivery resulted in significant improvement in cognitive function in both the Morris water maze and contextual fear-conditioning. Further, in vivo gene expression was robust in the entorhinal cortex and, via axonal transport, led to elevations of BDNF levels in hippocampus. BDNF gene delivery in APP transgenic mice normalized synaptophysin levels in the entorhinal cortex and hippocampus and increased neuronal Erk expression. Gene array analysis indicated significant perturbations in >100 sets of genes related to cellular function and survival in APP transgenic mice compared to wild-type animals; BDNF gene delivery reversed 55% of APP-related gene perturbations toward patterns of wild-type mice in both the entorhinal and hippocampus. These findings identify restorative synaptic and behavioral effects of BDNF on neuronal circuitry involved in AD, in a mechanism acting independently of effects on amyloid plaque number. BDNF delivery to EC may represent a therapeutic means of addressing entorhinal and hippocampal degeneration in Alzheimer's disease.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2009065837