RESUMO
Deposition of amyloid-ß (Aß) in the brain can impair neuronal function and contribute to cognitive decline in Alzheimer's disease (AD). Here, we found that dopamine and the dopamine precursor levodopa (also called l-DOPA) induced Aß degradation in the brain. Chemogenetic approaches in mice revealed that the activation of dopamine release from ventral tegmental area (VTA) neurons increased the abundance and activity of the Aß-degrading enzyme neprilysin and reduced the amount of Aß deposits in the prefrontal cortex in a neprilysin-dependent manner. Aged mice had less dopamine and neprilysin in the anterior cortex, a decrease that was accentuated in AD model mice. Treating AD model mice with levodopa reduced Aß deposition and improved cognitive function. These observations demonstrate that dopamine promotes brain region-specific, neprilysin-dependent degradation of Aß, suggesting that dopamine-associated strategies have the potential to treat this aspect of AD pathology.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Dopamina , Neprilisina , Área Tegmentar Ventral , Neprilisina/metabolismo , Neprilisina/genética , Animais , Dopamina/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Camundongos , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Levodopa/farmacologia , Encéfalo/metabolismo , Camundongos Transgênicos , Modelos Animais de Doenças , Humanos , Proteólise/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , MasculinoRESUMO
Alzheimer's disease (AD) involves reduced glutathione levels, causing oxidative stress and contributing to neuronal cell death. Our prior research identified diminished glutamate-cysteine ligase catalytic subunit (GCLC) as linked to cell death. However, the effect of GCLC on AD features such as amyloid and tau pathology remained unclear. To address this, we investigated amyloid pathology and tau pathology in mice by combining neuron-specific conditional GCLC knockout mice with amyloid precursor protein (App) knockin (KI) or microtubule-associated protein tau (MAPT) KI mice. Intriguingly, GCLC knockout resulted in an increased Aß42/40 ratio. Additionally, GCLC deficiency in MAPT KI mice accelerated the oligomerization of tau through intermolecular disulfide bonds. These findings suggest that the decline in glutathione levels, due to aging or AD pathology, may contribute to the progression of AD.