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.
Highlights
The transgenic APPswe/PS1dE9 (APdE9) mouse line is a widely used model of Alzheimer’s disease (AD)
The present study addressed the logical question whether a decrease in the main TrkB ligand, Brain-derived neurotrophic factor (BDNF), would lead to aggravated spatial memory impairment in AD model mice, which would further indicate its role in AD pathology
In cases where we focused on the effect of Bdnf deficiency alone, Bdnf+/2 mice (B-) were compared to Bw mice of the corresponding APdE9 gene status using Student’s t-test
Summary
The transgenic APPswe/PS1dE9 (APdE9) mouse line is a widely used model of Alzheimer’s disease (AD). Amyloid plaques gradually develop in the cortex and hippocampus of APdE9 mice starting at 4 months of age [1], which is followed by memory impairment 4–8 months later [2,3]. These mice recapitulate the order of pathological events in AD patients, in whom amyloid plaque formation can progress for years before memory impairment becomes manifested, as revealed by recent PET imaging studies with amyloid binding ligand [4,5]. The role of BDNF in the regulation of synaptogenesis and neuronal plasticity and maintenance in several brain areas and neuronal subsystems has been well characterized [6,10,11]
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