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The Journal of Neuroscience, July 22, 2009, 29(29):9321-9329; doi:10.1523/JNEUROSCI.4736-08.2009

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Neurobiology of Disease
Decreased Brain-Derived Neurotrophic Factor Depends on Amyloid Aggregation State in Transgenic Mouse Models of Alzheimer's Disease

Shiyong Peng,¹ Diego J. Garzon,¹ Monica Marchese,¹ William Klein,^2,3 Stephen D. Ginsberg,⁴ Beverly M. Francis,^5,6 Howard T. J. Mount,^5,6 Elliott J. Mufson,⁷ Ahmad Salehi,⁸ and Margaret Fahnestock¹

¹Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada, ²Institute for Neuroscience, Northwestern University, Evanston, Illinois 60611, ³Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, ⁴Nathan Kline Institute, New York University School of Medicine, Orangeburg, New York 10962, ⁵Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario M5S 3H2, Canada, ⁶Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada, ⁷Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, and ⁸Department of Neurology, Stanford University, Stanford, California 94305

Correspondence should be addressed to Dr. Margaret Fahnestock, Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada. E-mail: Email: fahnest{at}mcmaster.ca

Downregulation of brain-derived neurotrophic factor (BDNF) in the cortex occurs early in the progression of Alzheimer's disease (AD). Since BDNF plays a critical role in neuronal survival, synaptic plasticity, and memory, BDNF reduction may contribute to synaptic and cellular loss and memory deficits characteristic of AD. In vitro evidence suggests that amyloid-β (Aβ) contributes to BDNF downregulation in AD, but the specific Aβ aggregation state responsible for this downregulation in vivo is unknown. In the present study, we examined cortical levels of BDNF mRNA in three different transgenic AD mouse models harboring mutations in APP resulting in Aβ overproduction, and in a genetic mouse model of Down syndrome. Two of the three Aβ transgenic strains (APP^NLh and TgCRND8) exhibited significantly decreased cortical BDNF mRNA levels compared with wild-type mice, whereas neither the other strain (APP^swe/PS-1) nor the Down syndrome mouse model (Ts65Dn) was affected. Only APP^NLh and TgCRND8 mice expressed high Aβ₄₂/Aβ₄₀ ratios and larger SDS-stable Aβ oligomers (115 kDa). TgCRND8 mice exhibited downregulation of BDNF transcripts III and IV; transcript IV is also downregulated in AD. Furthermore, in all transgenic mouse strains, there was a correlation between levels of large oligomers, Aβ₄₂/Aβ₄₀, and severity of BDNF decrease. These data show that the amount and species of Aβ vary among transgenic mouse models of AD and are negatively correlated with BDNF levels. These findings also suggest that the effect of Aβ on decreased BDNF expression is specific to the aggregation state of Aβ and is dependent on large oligomers.

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Received Sept. 29, 2008; revised April 26, 2009; accepted May 14, 2009.

Correspondence should be addressed to Dr. Margaret Fahnestock, Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada. E-mail: Email: fahnest{at}mcmaster.ca

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