Dataset Information

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

ABSTRACT: Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline and the pathologic accumulations of amyloid ?-peptide (A?) and hyperphosphorylated tau in Alzheimer's disease (AD). To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the ?-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? toxicity. ?-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? 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.

SUBMITTER: Liu D

PROVIDER: S-EPMC3596471 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Liu Dong D Pitta Michael M Jiang Haiyang H Lee Jong-Hwan JH Zhang Guofeng G Chen Xinzhi X Kawamoto Elisa M EM Mattson Mark P MP

Neurobiology of aging 20121225 6

Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline and the pathologic accumulations of amyloid β-peptide (Aβ) and hyperphosphorylated tau in Alzheimer's disease (AD). To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the β-nicotinamide adenine dinucleotide precursor nicotinamide on brain cell mitochondrial function and macroautophagy, bioenergetics-related signaling, and cognitive performance were st ...[more]

PMID: 23273573

Similar Datasets

Project description:Alzheimer disease (AD) is the most common neurodegenerative disease. An imbalance between the production and clearance of Aβ (amyloid beta) is considered to be actively involved in AD pathogenesis. Macroautophagy/autophagy is a major cellular pathway leading to the removal of aggregated proteins, and upregulation of autophagy represents a plausible therapeutic strategy to combat overproduction of neurotoxic Aβ. PPARA/PPARα (peroxisome proliferator activated receptor alpha) is a transcription factor that regulates genes involved in fatty acid metabolism and activates hepatic autophagy. We hypothesized that PPARA regulates autophagy in the nervous system and PPARA-mediated autophagy affects AD. We found that pharmacological activation of PPARA by the PPARA agonists gemfibrozil and Wy14643 induces autophagy in human microglia (HM) cells and U251 human glioma cells stably expressing the human APP (amyloid beta precursor protein) mutant (APP-p.M671L) and this effect is PPARA-dependent. Administration of PPARA agonists decreases amyloid pathology and reverses memory deficits and anxiety symptoms in APP-PSEN1ΔE9 mice. There is a reduced level of soluble Aβ and insoluble Aβ in hippocampus and cortex tissues from APP-PSEN1ΔE9 mice after treatment with either gemfibrozil or Wy14643, which promoted the recruitment of microglia and astrocytes to the vicinity of Aβ plaques and enhanced autophagosome biogenesis. These results indicated that PPARA is an important factor regulating autophagy in the clearance of Aβ and suggested gemfibrozil be assessed as a possible treatment for AD.Abbreviation: Aβ: amyloid beta; ACTB: actin beta; ADAM10: ADAM metallopeptidase domain 10; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; ANOVA: analysis of variance; APOE: apolipoprotein E; APP: amyloid beta precursor protein; APP-PSEN1ΔE9: APPswe/PSEN1dE9; BAFA1: bafilomycin A1; BDNF: brain derived neurotrophic factor; BECN1: beclin 1; CD68: CD68 molecule; CREB1: cAMP responsive element binding protein 1; DAPI: 4',6-diamidino-2-phenylindole; DLG4/PSD-95: discs large MAGUK scaffold protein 4; DMSO: dimethyl sulfoxide; ELISA: enzyme linked immunosorbent assay; FDA: U.S. Food and Drug Administration; FKBP5: FK506 binding protein 5; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; gemfibrozil: 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid; GFAP: glial fibrillary acidic protein; GLI2/THP1: GLI family zinc finger 2; HM: human microglia; IL6: interleukin 6; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; NC: negative control; OQ: opposite quadrant; PPARA/PPARα, peroxisome proliferator activated receptor alpha; PSEN1/PS1: presenilin 1; SEM: standard error of the mean; SQSTM1: sequestosome 1; SYP: synaptophysin; TFEB: transcription factor EB; TNF/TNF-α: tumor necrosis factor; TQ: target quadrant; WT: wild type; Wy14643: 2-[4-chloro-6-(2,3-dimethylanilino)pyrimidin-2-yl]sulfanylacetic acid.

Project description:BackgroundDespite its identification as a key checkpoint regulator of microglial activation in Alzheimer's disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Aβ driven neurodegeneration, including accumulation of hyperphosphorylated tau is not well understood.MethodologyAccumulation of soluble and insoluble Aβ species, microglial activation, synaptic dysregulation, and neurodegeneration is investigated in 4- and 6-month old 5xFAD;Cx3cr1+/+ and 5xFAD;Cx3cr1-/- mice using immunohistochemistry, western blotting, transcriptomic and quantitative real time PCR analyses of purified microglia. Flow cytometry based, in-vivo Aβ uptake assays are used for characterization of the effects of CX3CR1-signaling on microglial phagocytosis and lysosomal acidification as indicators of clearance of methoxy-X-04+ fibrillar Aβ. Lastly, we use Y-maze testing to analyze the effects of Cx3cr1 deficiency on working memory.ResultsDisease progression in 5xFAD;Cx3cr1-/- mice is characterized by increased deposition of filamentous plaques that display defective microglial plaque engagement. Microglial Aβ phagocytosis and lysosomal acidification in 5xFAD;Cx3cr1-/- mice is impaired in-vivo. Interestingly, Cx3cr1 deficiency results in heighted accumulation of neurotoxic, oligomeric Aβ, along with severe neuritic dystrophy, preferential loss of post-synaptic densities, exacerbated tau pathology, neuronal loss and cognitive impairment. Transcriptomic analyses using cortical RNA, coupled with qRT-PCR using purified microglia from 6 month-old mice indicate dysregulated TGFβ-signaling and heightened ROS metabolism in 5xFAD;Cx3cr1-/- mice. Lastly, microglia in 6 month-old 5xFAD;Cx3cr1-/- mice express a 'degenerative' phenotype characterized by increased levels of Ccl2, Ccl5, Il-1β, Pten and Cybb along with reduced Tnf, Il-6 and Tgfβ1 mRNA.ConclusionsCx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby triggering increased accumulation of neurotoxic Aβ species. Furthermore, loss of Cx3cr1 results in microglial dysfunction typified by dampened TGFβ-signaling, increased oxidative stress responses and dysregulated pro-inflammatory activation. Our results indicate that Aβ-driven microglial dysfunction in Cx3cr1-/- mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation and impairs working memory.

Project description:Mitochondria are highly specialized organelles essential for the synapse, and their impairment contributes to the neurodegeneration in Alzheimer's disease (AD). Previously, we studied the role of caspase-3-cleaved tau in mitochondrial dysfunction in AD. In neurons, the presence of this AD-relevant tau form induced mitochondrial fragmentation with a concomitant reduction in the expression of Opa1, a mitochondrial fission regulator. More importantly, we showed that caspase-cleaved tau affects mitochondrial transport, decreasing the number of moving mitochondria in the neuronal processes without affecting their velocity rate. However, the molecular mechanisms involved in these events are unknown. We studied the possible role of motor proteins (kinesin 1 and dynein) and mitochondrial protein adaptors (RhoT1/T2, syntaphilin, and TRAK2) in the mitochondrial transport failure induced by caspase-cleaved tau. We expressed green fluorescent protein (GFP), GFP-full-length, and GPF-caspase-3-cleaved tau proteins in rat hippocampal neurons and immortalized cortical neurons (CN 1.4) and analyzed the expression and localization of these proteins involved in mitochondrial transport regulation. We observed that hippocampal neurons expressing caspase-cleaved tau showed a significant accumulation of a mitochondrial population in the soma. These changes were accompanied by evident mitochondrial bioenergetic deficits, including depolarization, oxidative stress, and a significant reduction in ATP production. More critically, caspase-cleaved tau significantly decreased the expression of TRAK2 in immortalized and primary hippocampal neurons without affecting RhoT1/T2 and syntaphilin levels. Also, when we analyzed the expression of motor proteins-Kinesin 1 (KIF5) and Dynein-we did not detect changes in their expression, localization, and binding to the mitochondria. Interestingly, the expression of truncated tau significantly increases the association of TRAK2 with mitochondria compared with neuronal cells expressing full-length tau. Altogether these results indicate that caspase-cleaved tau may affect mitochondrial transport through the increase of TRAK2-mitochondria binding and reduction of ATP production available for the process of movement of these organelles. These observations are novel and represent a set of exciting findings whereby tau pathology could affect mitochondrial distribution in neurons, an event that may contribute to synaptic failure observed in AD.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets