Leonard Davis School of Gerontology, Department of Psychology, & Department of Biomedical Engineering, University of Southern California, 3715 McClintock Ave, Los Angeles, CA 90089, United States.
Semin Cell Dev Biol. 2021 Aug;116:108-124. doi: 10.1016/j.semcdb.2021.05.013. Epub 2021 Jun 4.
Many believe that engaging in novel and mentally challenging activities promotes brain health and prevents Alzheimer's disease in later life. However, mental stimulation may also have risks as well as benefits. As neurons release neurotransmitters, they often also release amyloid peptides and tau proteins into the extracellular space. These by-products of neural activity can aggregate into the tau tangle and amyloid plaque signatures of Alzheimer's disease. Over time, more active brain regions accumulate more pathology. Thus, increasing brain activity can have a cost. But the neuromodulator noradrenaline, released during novel and mentally stimulating events, may have some protective effects-as well as some negative effects. Via its inhibitory and excitatory effects on neurons and microglia, noradrenaline sometimes prevents and sometimes accelerates the production and accumulation of amyloid-β and tau in various brain regions. Both α2A- and β-adrenergic receptors influence amyloid-β production and tau hyperphosphorylation. Adrenergic activity also influences clearance of amyloid-β and tau. Furthermore, some findings suggest that Alzheimer's disease increases noradrenergic activity, at least in its early phases. Because older brains clear the by-products of synaptic activity less effectively, increased synaptic activity in the older brain risks accelerating the accumulation of Alzheimer's pathology more than it does in the younger brain.
许多人认为，参与新颖的、具有挑战性的精神活动可以促进大脑健康，预防老年痴呆症。然而，精神刺激也可能既有风险也有好处。当神经元释放神经递质时，它们通常也会将淀粉样肽和tau 蛋白释放到细胞外空间。这些神经活动的副产物可以聚集形成老年痴呆症的 tau 缠结和淀粉样斑块特征。随着时间的推移，更活跃的大脑区域会积累更多的病变。因此，增加大脑活动可能会有代价。但是，在新颖和精神刺激的事件中释放的神经调节剂去甲肾上腺素可能具有一些保护作用——以及一些负面影响。通过对神经元和小胶质细胞的抑制和兴奋作用，去甲肾上腺素有时可以预防，有时可以加速各种大脑区域中淀粉样蛋白-β和 tau 的产生和积累。α2A-和 β-肾上腺素受体都会影响淀粉样蛋白-β的产生和 tau 的过度磷酸化。肾上腺素能活动还会影响淀粉样蛋白-β和 tau 的清除。此外，一些发现表明，老年痴呆症至少在其早期阶段会增加去甲肾上腺素能活性。由于老年大脑清除突触活动副产物的效果较差，因此，与年轻大脑相比，老年大脑中增加的突触活动更有可能加速老年痴呆症病理的积累。
