The Impact of Bdnf Gene Deficiency to the Memory Impairment and Brain Pathology of APPswe/PS1dE9 Mouse Model of Alzheimer’s Disease

Abstract

Brain-derived neurotrophic factor (BDNF) importantly regulates learning and memory and supports the survival of injured neurons. Reduced BDNF levels have been detected in the brains of Alzheimer’s disease (AD) patients but the exact role of BDNF in the pathophysiology of the disorder remains obscure. We have recently shown that reduced signaling of BDNF receptor TrkB aggravates memory impairment in APPswe/PS1dE9 (APdE9) mice, a model of AD. The present study examined the influence of Bdnf gene deficiency (heterozygous knockout) on spatial learning, spontaneous exploratory activity and motor coordination/balance in middle-aged male and female APdE9 mice. We also studied brain BDNF protein levels in APdE9 mice in different ages showing progressive amyloid pathology. Both APdE9 and Bdnf mutations impaired spatial learning in males and showed a similar trend in females. Importantly, the effect was additive, so that double mutant mice performed the worst. However, APdE9 and Bdnf mutations influenced spontaneous locomotion in contrasting ways, such that locomotor hyperactivity observed in APdE9 mice was normalized by Bdnf deficiency. Obesity associated with Bdnf deficiency did not account for the reduced hyperactivity in double mutant mice. Bdnf deficiency did not alter amyloid plaque formation in APdE9 mice. Before plaque formation (3 months), BDNF protein levels where either reduced (female) or unaltered (male) in the APdE9 mouse cortex. Unexpectedly, this was followed by an age-dependent increase in mature BDNF protein. Bdnf mRNA and phospho-TrkB levels remained unaltered in the cortical tissue samples of middle-aged APdE9 mice. Immunohistological studies revealed increased BDNF immunoreactivity around amyloid plaques indicating that the plaques may sequester BDNF protein and prevent it from activating TrkB. If similar BDNF accumulation happens in human AD brains, it would suggest that functional BDNF levels in the AD brains are even lower than reported, which could partially contribute to learning and memory problems of AD patients.

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

“…6c) or WT mice (Fig. 6e and 6g) (Rantamäki et al 2013). Therefore, we determined whether BDNF was downregulated in the hippocampus of aged APP/PS1 mice.…”

Neurotrophin regulation of Alzheimer's disease pathology

“…Extensive literature exists of multiple transgenic mouse lines with increased or decreased BDNF signalling and behavioural phenotypes as models of various mood disorders (reviewed in Lindholm and Castren, 2014), demonstrating a tight link between BDNF levels and cognitive processes. Moreover, an exacerbation of memory impairments in a Morris water maze has been reported in APP/PS1 mice with a global decrease in BDNF (BDNF +/-mice) (Rantamaki et al, 2013). However in the present chapter, we demonstrated that knockdown of hippocampal BDNF in APP/PS1 mice did not result in a change in Y-maze performance compared to saline-injected transgenic controls.…”

“…The authors of this work reported no increase in amyloid or tau pathology driven by the reduction of BDNF protein in these mice, however presynaptic markers such as synaptophysin were decreased (Castello et al, 2012). These results are supported by APP/PS1 x BDNF +/-mice which similarly showed no alteration in amyloid pathology but displayed exacerbated memory impairments in a Morris water maze task (Rantamaki et al, 2013). Interestingly, the latter study reported a possible mechanism by which Aβ might induce BDNF reduction -through BDNF protein sequestration into amyloid plaques (Rantamaki et al, 2013).…”

“…These results are supported by APP/PS1 x BDNF +/-mice which similarly showed no alteration in amyloid pathology but displayed exacerbated memory impairments in a Morris water maze task (Rantamaki et al, 2013). Interestingly, the latter study reported a possible mechanism by which Aβ might induce BDNF reduction -through BDNF protein sequestration into amyloid plaques (Rantamaki et al, 2013). Together these results suggest that the reduced BDNF levels found in AD are a consequence of AD pathology, yet they do contribute to impairments in memory.…”

“…For example, compensatory neurotrophic signalling may have occured over the course of a BDNF -/+ mouse's life which might mitigate any impact of the reduced BDNF on AD features. Indeed, this idea is supported by the demonstration that, despite the mice having reduced BDNF levels, they did not have changes in BDNF-related signalling (Castello et al, 2012, Rantamaki et al, 2013. Therefore, while it appears that BDNF plays a contributory role in cognitive deficits in AD mice, it is as yet too early to conclude that BDNF does not have a causative role.…”