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

doi:10.1038/nm.1912

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

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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 language	English
Pages (from-to)	331-337
Number of pages	7
Journal	Nature medicine
Volume	15
Issue number	3
DOIs	https://doi.org/10.1038/nm.1912
State	Published - Mar 2009

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Nagahara, A. H., Merrill, D. A., Coppola, G., Tsukada, S., Schroeder, B. E., Shaked, G. M., Wang, L., Blesch, A., Kim, A., Conner, J. M., Rockenstein, E., Chao, M. V., Koo, E. H., Geschwind, D., Masliah, E., Chiba, A. A., & Tuszynski, M. H. (2009). Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nature medicine, 15(3), 331-337. https://doi.org/10.1038/nm.1912

@article{09768c499b554a02a611e643a25d8c6a,

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

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.",

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

note = "Funding Information: We thank C. Glabe (University of California, Irvine) for Ab1–42 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{\textquoteright}s Association, the State of California (04-35530), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and The Shiley Family Foundation.",

year = "2009",

month = mar,

doi = "10.1038/nm.1912",

language = "English",

volume = "15",

pages = "331--337",

journal = "Nature medicine",

issn = "1078-8956",

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Nagahara, AH, Merrill, DA, Coppola, G, Tsukada, S, Schroeder, BE, Shaked, GM, Wang, L, Blesch, A, Kim, A, Conner, JM, Rockenstein, E, Chao, MV, Koo, EH, Geschwind, D, Masliah, E, Chiba, AA & Tuszynski, MH 2009, 'Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease', Nature medicine, vol. 15, no. 3, pp. 331-337. https://doi.org/10.1038/nm.1912

TY - JOUR

T1 - Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease

AU - Nagahara, Alan H.

AU - Merrill, David A.

AU - Coppola, Giovanni

AU - Tsukada, Shingo

AU - Schroeder, Brock E.

AU - Shaked, Gideon M.

AU - Wang, Ling

AU - Blesch, Armin

AU - Kim, Albert

AU - Conner, James M.

AU - Rockenstein, Edward

AU - Chao, Moses V.

AU - Koo, Edward H.

AU - Geschwind, Daniel

AU - Masliah, Eliezer

AU - Chiba, Andrea A.

AU - Tuszynski, Mark H.

N1 - Funding Information: We thank C. Glabe (University of California, Irvine) for Ab1–42 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.

PY - 2009/3

Y1 - 2009/3

N2 - 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.

AB - 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.

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U2 - 10.1038/nm.1912

DO - 10.1038/nm.1912

M3 - Article

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AN - SCOPUS:62049083420

SN - 1078-8956

VL - 15

SP - 331

EP - 337

JO - Nature medicine

JF - Nature medicine

IS - 3

ER -

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

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