| Abstract No.: | B-C2112 |
| Country: | Canada |
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| Title: | PROTOFIBRILS DOWN-REGULATE BRAIN-DERIVED NEUROTROPHIC FACTOR IN ALZHEIMER’S DISEASE |
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| Authors/Affiliations: | 1 Shiyong Peng; 1 Diego Garzon; 1 Monica Marchese; 2 William Klein; 3 Stephen Ginsberg; 4 Beverly Francis; 4 Howard Mount; 5 Elliott Mufson; 6 Ahmad Salehi; 1 Margaret Fahnestock*;
1 McMaster University, Hamilton, ON, Canada; 2 Nathan Kline Institute, NYU, USA; 3 Northwestern University, Evanston,USA; 4 Norwestern University, Evanston, USA; 5 Rush University Medical Center, Stanford, CA, USA; 6 Stanford University, Stanford, CA, USA; 7 University of Toronto, ON, Canada
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| Content: | In Alzheimer’s disease (AD), monomers of amyloid-β (Aß) protein, derived by proteolytic cleavage of amyloid precursor protein, aggregate to form oligomers, protofibrils and finally insoluble fibrils, which accumulate to form senile plaques. All oligomers and protofibrils are termed amyloid-derived diffusible ligands (ADDLs). ADDLs are neurotoxic and are implicated in neuronal dysfunction and synaptic loss in AD. However, the mechanism by which ADDLs are toxic to neurons is unclear. Brain-derived neurotrophic factor (BDNF) is required for the survival, maintenance and function of hippocampal, cortical and basal forebrain neurons; its modulation of synaptic plasticity in hippocampus and cortex is the basis of memory and learning consolidation which is compromised in AD. We previously showed that BDNF mRNA and protein are significantly decreased by 30% in the early stages and up to 60% in late stages of AD. We also demonstrated down-regulation of BDNF in cell culture following application of Aβ oligomers but not fibrils. To examine whether BDNF is down-regulated by over-expression of Aβ in vivo, we measured BDNF mRNA levels in three different AD transgenic mouse models, APPNLh/PS1P264L, APPswe/PS1M146V and TgCRND8, and in Ts65Dn mice, a trisomy 16 mouse model of Down’s syndrome and AD. PCR analysis revealed BDNF down-regulation in the APPNLh/PS1P264L and TgCRND8 mice but not in the APPswe/PS1M146V or Ts65Dn mice. To address these differences in BDNF down-regulation patterns, we further examined the forms and quantity of aggregated Aβ in these models by semi-quantitative Western blotting. We found that protofibrils were significantly higher in those AD mouse models exhibiting BDNF down-regulation than in those with normal BDNF levels. In fact, higher amounts of protofibrils correlated with lower BDNF levels. To translate these findings to the human condition, we evaluated cortical brain samples from subjects who died with a clinical diagnosis of non-cognitive impairment (NCI; n=14), mild cognitive impairment (MCI; n=13), or AD (n=14). Semi-quantitative Western blotting revealed half as many protofibrils in NCI as in MCI and AD subjects. Levels of protofibrils were negatively correlated with BDNF levels. Interestingly, protofibril levels were also negatively correlated with the Mini Mental State Examination and Global Cognitive Severity scales, measures of cognitive function. These results suggest that protofibrils play a pivotal role in BDNF down-regulation seen in vitro and in vivo and likely contribute to the cognitive dysfunction seen during the progression of AD. |
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