Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: evidence for improved neuronal bioenergetics and autophagy procession

作者：Liu Dong; Pitta Michael; Jiang Haiyang; Lee Jong Hwan; Zhang Guofeng; Chen Xinzhi; Kawamoto Elisa M; Mattson Mark P^*

来源：Neurobiology of Aging, 2013, 34(6): 1564-1580.

DOI：10.1016/j.neurobiolaging.2012.11.020

• NAD(+)
• Nicotinamide
• Mitochondria
• DLP1
• Autophagy
• Lysosome
• 3xTgAD
• p-Akt
• CREB
• Learning and memory

Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline and the pathologic accumulations of amyloid beta-peptide (A beta) and hyperphosphorylated tau in Alzheimer%26apos;s disease (AD). To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the beta-nicotinamide adenine dinucleotide precursor nicotinamide on brain cell mitochondrial function and macroautophagy, bioenergetics-related signaling, and cognitive performance were studied in cultured neurons and in a mouse model of AD. Oxidative stress resulted in decreased mitochondrial mass, mitochondrial degeneration, and autophagosome accumulation in neurons. Nicotinamide preserved mitochondrial integrity and autophagy function, and reduced neuronal vulnerability to oxidative/metabolic insults and A beta toxicity. beta-Nicotinamide adenine dinucleotide biosynthesis, autophagy, and phosphatidylinositol-3-kinase signaling were required for the neuroprotective action of nicotinamide. Treatment of 3xTgAD mice with nicotinamide for 8 months resulted in improved cognitive performance, and reduced A beta and hyperphosphorylated tau pathologies in hippocampus and cerebral cortex. Nicotinamide treatment preserved mitochondrial integrity, and improved autophagy-lysosome procession by enhancing lysosome/autolysosome acidification to reduce autophagosome accumulation. Treatment of 3xTgAD mice with nicotinamide resulted in elevated levels of activated neuroplasticity-related kinases (protein kinase B [Akt] and extracellular signal-regulated kinases) and the transcription factor cyclic adenosine monophosphate (AMP) response element-binding protein in the hippocampus and cerebral cortex. Thus, nicotinamide suppresses AD pathology and cognitive decline in a mouse model of AD by a mechanism involving improved brain bioenergetics with preserved functionality of mitochondria and the autophagy system. Published by Elsevier Inc.

• 出版日期2013-6