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

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-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 (APPNLh 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 APPNLh 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.

P1–100: CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease

“…S6). These results are consistent with previous reports of reduced BDNF levels in AD brains and other animal models (27)(28)(29). We next assessed how BDNF protein levels change in response to CBP gene transfer.…”

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

“…Evidence has suggested that dysfunction of BDNF is a possible contributor to the pathology and symptoms of AD (Tapia-Arancibia et al 2008). BDNF is found to be decreased in APP/PS1 mice even in the early stages of AD-like pathology (Peng et al 2009;Hsiao et al 2014). Apart from BDNF, other neurotrophic factors, such as nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF), are also involved in normal aging and AD (Allen et al 2013;Budni et al 2015).…”

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

“…A growing body of evidence indicates that BDNF levels are decreased in brains of AD patients (Hu and Russek, 2008;Peng et al, 2005;Zuccato and Cattaneo, 2009) and APP transgenic mice (Francis et al, 2010;Peng et al, 2009). We first characterized changes in BDNF levels in the 5XFAD transgenic mouse model at different ages ranging from 3 to 18 months (Figure 1).…”