title: 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.
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Tomi
authors.initials: T
authors.lastname: Rantamäki
authors.forename: Susanna
authors.initials: S
authors.lastname: Kemppainen
authors.forename: Henri
authors.initials: H
authors.lastname: Autio
authors.forename: Saara
authors.initials: S
authors.lastname: Stavén
authors.forename: Hennariikka
authors.initials: H
authors.lastname: Koivisto
authors.forename: Masami
authors.initials: M
authors.lastname: Kojima
authors.forename: Hanna
authors.initials: H
authors.lastname: Antila
authors.forename: Pasi O
authors.initials: PO
authors.lastname: Miettinen
authors.forename: Elisa
authors.initials: E
authors.lastname: Kärkkäinen
authors.forename: Nina
authors.initials: N
authors.lastname: Karpova
authors.forename: Liisa
authors.initials: L
authors.lastname: Vesa
authors.forename: Lothar
authors.initials: L
authors.lastname: Lindemann
authors.forename: Marius C
authors.initials: MC
authors.lastname: Hoener
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.forename: Eero
authors.initials: E
authors.lastname: Castrén
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004777:Environment; D005260:Female; D006801:Humans; D006948:Hyperkinesis / Q000235:genetics; D008297:Male; D018782:Maze Learning; D008568:Memory; D008569:Memory Disorders / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid; D053764:Presenilin-1 / Q000235:genetics; D011597:Psychomotor Performance
chemical_list: D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; D053764:Presenilin-1