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

Abstract

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.