Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer's disease
Shiyong Peng,Diego J. Garzon,Diego J. Garzon,Monica Marchese,William L. Klein,Stephen D. Ginsberg,Beverly M. Francis,Howard T.J. Mount,Elliott J. Mufson,Ahmad Salehi,Margaret Fahnestock +10 more
TL;DR: Cortical levels of BDNF mRNA are examined in three different transgenic AD mouse models harboring mutations in APP resulting in Aβ overproduction, and in a genetic mouse model of Down syndrome to suggest the effect of Aβ on decreased BDNF expression is specific to the aggregation state of A β and is dependent on large oligomers.
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Abstract: 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-beta (A beta) contributes to BDNF downregulation in AD, but the specific A beta 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 A beta overproduction, and in a genetic mouse model of Down syndrome. Two of the three A beta 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 A beta(42)/A beta(40) ratios and larger SDS-stable A beta oligomers (approximately 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, A beta(42)/A beta(40), and severity of BDNF decrease. These data show that the amount and species of A beta vary among transgenic mouse models of AD and are negatively correlated with BDNF levels. These findings also suggest that the effect of A beta on decreased BDNF expression is specific to the aggregation state of A beta and is dependent on large oligomers.
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References
A specific amyloid-|[beta]| protein assembly in the brain impairs memory
Sylvain Lesné,Ming Teng Koh,Linda Kotilinek,Rakez Kayed,Charles G. Glabe,Austin J. Yang,Michela Gallagher,Karen H. Ashe +7 more
TL;DR: It is found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-β assembly, which is proposed to be Aβ*56 (Aβ star 56), which may contribute to cognitive deficits associated with Alzheimer's disease.
2.8K
The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease.
TL;DR: Kinetic studies of aggregation by naturally occurring beta protein variants and four model peptides demonstrate that amyloid formation, like crystallization, is a nucleation-dependent phenomenon and suggest that nucleation may be the rate-determining step of in vivo amyloidsogenesis.
2.1K
A beta oligomers - a decade of discovery.
TL;DR: Accumulating evidence suggests that soluble forms of Aβ are indeed the proximate effectors of synapse loss and neuronal injury in Alzheimer’s disease.
2K