RESUMO
Adult hippocampal neurogenesis (AHN) is impaired before the onset of Alzheimer's disease (AD) pathology. We found that exercise provided cognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN and elevating levels of brain-derived neurotrophic factor (BDNF). Neither stimulation of AHN alone, nor exercise, in the absence of increased AHN, ameliorated cognition. We successfully mimicked the beneficial effects of exercise on AD mice by genetically and pharmacologically inducing AHN in combination with elevating BDNF levels. Suppressing AHN later led to worsened cognitive performance and loss of preexisting dentate neurons. Thus, pharmacological mimetics of exercise, enhancing AHN and elevating BDNF levels, may improve cognition in AD. Furthermore, applied at early stages of AD, these mimetics may protect against subsequent neuronal cell death.
Assuntos
Doença de Alzheimer/psicologia , Doença de Alzheimer/terapia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição , Exercício Físico , Hipocampo/citologia , Neurogênese , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Carbazóis/administração & dosagem , Carbazóis/farmacologia , Morte Celular , Modelos Animais de Doenças , Feminino , Fibronectinas , Humanos , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Condicionamento Físico Animal , Proteína Wnt3/genéticaRESUMO
The generation of Aß, the main component of senile plaques in Alzheimer's disease (AD), is precluded by α-secretase cleavage within the Aß domain of the amyloid precursor protein (APP). We identified two rare mutations (Q170H and R181G) in the prodomain of the metalloprotease, ADAM10, that cosegregate with late-onset AD (LOAD). Here, we addressed the pathogenicity of these mutations in transgenic mice expressing human ADAM10 in brain. In Tg2576 AD mice, both mutations attenuated α-secretase activity of ADAM10 and shifted APP processing toward ß-secretase-mediated cleavage, while enhancing Aß plaque load and reactive gliosis. We also demonstrated ADAM10 expression potentiates adult hippocampal neurogenesis, which is reduced by the LOAD mutations. Mechanistically, both LOAD mutations impaired the molecular chaperone activity of ADAM10 prodomain. Collectively, these findings suggest that diminished α-secretase activity, owing to LOAD ADAM10 prodomain mutations, leads to AD-related pathology, strongly supporting ADAM10 as a promising therapeutic target for this devastating disease.
Assuntos
Proteínas ADAM/genética , Proteínas ADAM/fisiologia , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/fisiologia , Peptídeos beta-Amiloides/metabolismo , Predisposição Genética para Doença/genética , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Chaperonas Moleculares/metabolismo , Mutação de Sentido Incorreto/genética , Proteínas ADAM/metabolismo , Proteína ADAM10 , Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/genética , Animais , Encéfalo/enzimologia , Encéfalo/patologia , Encéfalo/fisiologia , Feminino , Gliose/patologia , Hipocampo/fisiologia , Humanos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Chaperonas Moleculares/genética , Neurogênese/genética , Placa Amiloide/metabolismoRESUMO
The transmembrane protein CD33 is a sialic acid-binding immunoglobulin-like lectin that regulates innate immunity but has no known functions in the brain. We have previously shown that the CD33 gene is a risk factor for Alzheimer's disease (AD). Here, we observed increased expression of CD33 in microglial cells in AD brain. The minor allele of the CD33 SNP rs3865444, which confers protection against AD, was associated with reductions in both CD33 expression and insoluble amyloid beta 42 (Aß42) levels in AD brain. Furthermore, the numbers of CD33-immunoreactive microglia were positively correlated with insoluble Aß42 levels and plaque burden in AD brain. CD33 inhibited uptake and clearance of Aß42 in microglial cell cultures. Finally, brain levels of insoluble Aß42 as well as amyloid plaque burden were markedly reduced in APP(Swe)/PS1(ΔE9)/CD33(-/-) mice. Therefore, CD33 inactivation mitigates Aß pathology and CD33 inhibition could represent a novel therapy for AD.
