Letter abstract
Nature Medicine 15, 331 - 337 (2009)
Published online: 8 February 2009 | Corrected online: 12 February 2009 | doi:10.1038/nm.1912
Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease
Alan H Nagahara1,6, David A Merrill1,6, Giovanni Coppola2, Shingo Tsukada1, Brock E Schroeder1, Gideon M Shaked1, Ling Wang1, Armin Blesch1, Albert Kim3, James M Conner1, Edward Rockenstein1, Moses V Chao3, Edward H Koo1, Daniel Geschwind2, Eliezer Masliah1, Andrea A Chiba1,4 & Mark H Tuszynski1,5
Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimer's disease1, 2, 3. 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.
- Department of Neurosciences-0626, 9500 Gilman Drive, University of California–San Diego, La Jolla, California 92093, USA.
- Program in Neurogenetics, Department of Neurology, 710 Westwood Plaza, University of California–Los Angeles, Los Angeles, California 90095, USA.
- Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.
- Department of Cognitive Science-0515, 9500 Gilman Drive, University of California–San Diego, La Jolla, California 92093, USA.
- Veterans Affairs Medical Center, 3350 La Jolla Village Drive, San Diego, California 92161, USA.
- These authors contributed equally to this work.
Correspondence to: Mark H Tuszynski1,5 e-mail: mtuszynski@ucsd.edu
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