RESUMO
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 AßPP/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 AßPP/PS1 mice. Consistent with this, the postmortem histological analysis showed decreased brain parenchymal area in BDNF +/- mice but an increase in AßPP/PS1 mice. BDNF gene deficiency did not affect brain amyloid load or astrogliosis, but led to decreased dentate gyrus length, whereas AßPP/PS1 mice had significantly increased amyloid load, astrogliosis, and decreased neurogenesis. Distinct and layer-specific effects were found in the hippocampus of AßPP/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.
Assuntos
Doença de Alzheimer/patologia , Amiloidose/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Regulação da Expressão Gênica/genética , Fatores Etários , Precursor de Proteína beta-Amiloide/genética , Amiloidose/patologia , Análise de Variância , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Modelos Animais de Doenças , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Camundongos , Camundongos Transgênicos , Mutação/genética , Presenilina-1/genéticaRESUMO
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.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos da Memória/etiologia , Doença de Alzheimer/complicações , Precursor de Proteína beta-Amiloide/genética , Animais , Peso Corporal/genética , Encéfalo/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/deficiência , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Meio Ambiente , Feminino , Humanos , Hipercinese/genética , Masculino , Aprendizagem em Labirinto , Memória , Camundongos , Camundongos Transgênicos , Placa Amiloide , Presenilina-1/genética , Desempenho PsicomotorRESUMO
Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory. Levels of BDNF and its main receptor TrkB (TrkB.TK) have been reported to be decreased while the levels of the truncated TrkB (TrkB.T1) are increased in Alzheimer's disease. We show here that incubation with amyloid-ß increased TrkB.T1 receptor levels and decreased TrkB.TK levels in primary neurons. In vivo, APPswe/PS1dE9 transgenic mice (APdE9) showed an age-dependent relative increase in cortical but not hippocampal TrkB.T1 receptor levels compared with TrkB.TK. To investigate the role of TrkB isoforms in Alzheimer's disease, we crossed AP mice with mice overexpressing the truncated TrkB.T1 receptor (T1) or the full-length TrkB.TK isoform. Overexpression of TrkB.T1 in APdE9 mice exacerbated their spatial memory impairment while the overexpression of TrkB.TK alleviated it. These data suggest that amyloid-ß changes the ratio between TrkB isoforms in favor of the dominant-negative TrkB.T1 isoform both in vitro and in vivo and supports the role of BDNF signaling through TrkB in the pathophysiology and cognitive deficits of Alzheimer's disease.
