Brain Amyloidosis and BDNF Deficiency Have Opposite Effects on Brain Volumes in AβPP/PS1 Mice Both in vivo and ex vivo

Abstract

Magnetic resonance imaging (MRI) volumetry is widely used in Alzheimer's disease (AD) research and diagnostics alongside clinical assessment. Yet few MRI volumetry studies have been conducted in AD model mice with mixed results. We performed in vivo and ex vivo MRI and extensive postmortem histological analysis in transgenic mice derived from crossing amyloid plaque producing AβPP/PS1 mice with brain-derived neurotrophic factor (BDNF) +/- mice. This allowed us to compare developmental volumetric changes due to BDNF deficiency with progressive changes due to amyloid accumulation. We found decreased whole brain volume at 3 months and decreased cortical volume at both 3 and 8 months in vivo in BDNF +/- Tg mice but increased whole brain and cortical volumes at 8 months in AβPP/PS1 mice. Consistent with this, the postmortem histological analysis showed decreased brain parenchymal area in BDNF +/- mice but an increase in AβPP/PS1 mice. BDNF gene deficiency did not affect brain amyloid load or astrogliosis, but led to decreased dentate gyrus length, whereas AβPP/PS1 mice had significantly increased amyloid load, astrogliosis, and decreased neurogenesis. Distinct and layer-specific effects were found in the hippocampus of AβPP/PS1 and BDNF +/- mice. In contrast to human AD patients, brain atrophy in amyloid producing mice appears to be masked by volume increase due to amyloid accumulation and especially accompanying astrogliosis. Our results indicate that cortical MRI volumetry can be used to some extent as a proxy to progressive brain amyloidosis in preclinical studies.

Expression of brain-derived neurotrophic factor in kidneys from normal and cyclosporine-treated rats

“…BDNF functions as a neuroprotective agent against various neural insults through its role in neuronal cell proliferation, differentiation, and survival [ 1 , 29 ]. These actions have been confirmed by studies of exogenous BDNF administration or BDNF-deficient animals, which have shown the neuroprotective effects of BDNF in the central nervous system [ 30 – 32 ]. However, the role of BDNF in the kidney is largely unknown.…”

APPswe/PS1dE9 mice with cortical amyloid pathology show a reduced NAA/Cr ratio without apparent brain atrophy: A MRS and MRI study

“…This cortical neuron loss, however, was not reflected in the MRI based grey matter morphometry findings. In summary, the discrepant literature on MRI volumetric changes might strongly be dependent on the age and on the mouse strains, being used (Kärkkäinen et al, 2015). An alternative explanation for the discrepancy between missing atrophy despite neuronal loss may be the already described increase of glial cells (Manaye et al, 2007) in the corresponding brain regions that different to human AD may mask the effect of neuron loss on grey matter volume estimates from MRI.…”

“…Consistent with this assumption, APPswe/PS1dE9 mice of the current study presented high numbers of GFAP positive microglia and a high Aβ load. Further, it is reported that brain atrophy in amyloid producing mice appears to be masked by volume increase due to amyloid accumulation and especially accompanying astrogliosis (Kärkkäinen et al, 2015). …”

Effects of Neurotrophic Support and Amyloid-Targeted Combined Therapy on Adult Hippocampal Neurogenesis in a Transgenic Model of Alzheimer's Disease

“…A loss of BDNF transcript levels was demonstrated in 6–8 month old TgCRND8 mice [ 13 ]. AβPP/PS1 mice crossed with BDNF+/- mice exhibited decreased DCX+ cell density compared to those crossed with BDNF+/+ mice [ 49 ]. BDNF has the strongest affinity for the TrkB receptor, which is expressed on hippocampal NPCs [ 50 ], suggesting a direct effect of BDNF on proliferating cells in the dentate gyrus.…”