Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease

Alan H. Nagahara, David A. Merrill, Giovanni Coppola, Shingo Tsukada, Brock E. Schroeder, Gideon M. Shaked, Ling Wang, Armin Blesch, Albert Kim, James M. Conner, Edward Rockenstein, Moses V. Chao, Edward H. Koo, Daniel Geschwind, Eliezer Masliah, Andrea A. Chiba, Mark H. Tuszynski

Research output: Contribution to journalArticlepeer-review

836 Scopus citations

Abstract

Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimer's disease. Here we show broad neuroprotective effects of entorhinal brain-derived neurotrophic factor (BDNF) administration in several animal models of Alzheimer's disease, with extension of therapeutic benefits into the degenerating hippocampus. In amyloid-transgenic mice, BDNF gene delivery, when administered after disease onset, reverses synapse loss, partially normalizes aberrant gene expression, improves cell signaling and restores learning and memory. These outcomes occur independently of effects on amyloid plaque load. In aged rats, BDNF infusion reverses cognitive decline, improves age-related perturbations in gene expression and restores cell signaling. In adult rats and primates, BDNF prevents lesion-induced death of entorhinal cortical neurons. In aged primates, BDNF reverses neuronal atrophy and ameliorates age-related cognitive impairment. Collectively, these findings indicate that BDNF exerts substantial protective effects on crucial neuronal circuitry involved in Alzheimer's disease, acting through amyloid-independent mechanisms. BDNF therapeutic delivery merits exploration as a potential therapy for Alzheimer's disease.

Original languageEnglish
Pages (from-to)331-337
Number of pages7
JournalNature medicine
Volume15
Issue number3
DOIs
StatePublished - Mar 2009

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