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

Nature Medicine volume 15, pages 331–337 (2009)Cite this article

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Abstract

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.

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Figure 1: BDNF effects in APP-transgenic mice.
Figure 2: BDNF effects in aged rats.
Figure 3: BDNF effects on cell survival.
Figure 4: BDNF effects in primates.

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Change history

  • 12 February 2009

    In the version of this article initially published online, there was an error in the heat map in Figure 2h—the description ‘BDNF:aged’ applies only to the two rightmost columns, not the three rightmost columns. Additionally, some of the P values in the legends for Figure 1a, Figure 2b,f and Figure 3b,e were incorrect. Finally, ‘entorhinal’ was misspelled in Figure 1i. The errors have been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank C. Glabe (University of California, Irvine) for Aβ1–42 peptide. We thank D. Amaral and P. Lavenex for assistance with the primate perforant path model, K. Loew, T. Mead, R. Torres and M. Mateling for technical support, and F. Gao for data analysis. This work was supported by the US National Institutes of Health (AG10435), the California Regional Primate Research Center Base Grant, the Veterans Administration, the Alzheimer's Association, the State of California (04-35530), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and The Shiley Family Foundation.

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Author notes

  1. Alan H Nagahara and David A Merrill: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosciences-0626, 9500 Gilman Drive, University of California–San Diego, La Jolla, 92093, California, USA

    Alan H Nagahara, David A Merrill, Shingo Tsukada, Brock E Schroeder, Gideon M Shaked, Ling Wang, Armin Blesch, James M Conner, Edward Rockenstein, Edward H Koo, Eliezer Masliah, Andrea A Chiba & Mark H Tuszynski

  2. Department of Neurology, Program in Neurogenetics, 710 Westwood Plaza, University of California–Los Angeles, Los Angeles, 90095, California, USA

    Giovanni Coppola & Daniel Geschwind

  3. Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, 10016, New York, USA

    Albert Kim & Moses V Chao

  4. Department of Cognitive Science-0515, 9500 Gilman Drive, University of California–San Diego, La Jolla, 92093, California, USA

    Andrea A Chiba

  5. Veterans Affairs Medical Center, 3350 La Jolla Village Drive, San Diego, 92161, California, USA

    Mark H Tuszynski

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Contributions

A.H.N. contributed surgery, data collection, analysis and manuscript writing for all studies; D.A.M. contributed data collection, analysis and manuscript writing for aging studies; G.C. and D.G. contributed to array studies and analysis; S.T. contributed to in vitro Aβ toxicity studies; B.E.S., G.M.S. and E.K. contributed to Aβ in vitro toxicity studies and breeding and behavior of APP mice; L.W. contributed stereology of APP mice; A.B. generated gene expression vectors; A.K. and M.V.C. contributed western blot analysis in aged rats; J.M.C. contributed ELISA and biochemical analyses; E.R. contributed surgery of APP mice; E.M. contributed synaptophysin quantification and surgery in APP mice; A.A.C. contributed surgery and behavioral analysis in aged rats and manuscript writing; M.H.T. contributed experimental design, surgery in rats and primates, data analysis and manuscript writing.

Corresponding author

Correspondence to Mark H Tuszynski.

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Competing interests

M.H.T. is a scientific founder of Ceregene, Inc. and Trophin, Inc. Neither entity supported this research.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–4 and Supplementary Methods (PDF 647 kb)

Supplementary Data 1

Differentially expressed genes in APP-TG mice compared to WT, and effect of BDNF gene delivery (XLS 1038 kb)

Supplementary Data 2

Differentially expressed genes in aged rats compared to young, and effect of BDNF gene delivery to entorhinal cortex. (XLS 527 kb)

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Nagahara, A., Merrill, D., Coppola, G. et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med 15, 331–337 (2009). https://doi.org/10.1038/nm.1912

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