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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.

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