Nicotinamide Restores Cognition in Alzheimer's Disease Transgenic Mice via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-Phosphotau

“The sirtuin family of deacetylases is implicated in cellular pathways that influence longevity in yeast, C. elegans, Drosophila, and mammals (Tissenbaum and Guarente, 2001; Anderson et al., 2003; Howitz et al., 2003; Wood et al., 2004; Baur et al., 2006).”

“By 8 months, somatodendritic accumulation of phospho- and non-phosphotau also occurs in the hippocampus and amygdala, but not the cortex (Oddo et al., 2003).”

“Kim N. Green,1 Joan S. Steffan,2 Hilda Martinez-Coria,1 Xuemin Sun,3 Steven S. Schreiber,3,5 Leslie Michels Thompson,1,2,4 and Frank M. LaFerla1”

“Acetylation of histones and nonhistone transcription factors plays an important role in regulating chromatin condensation and gene transcription (Roth et al., 2001).”

“The sirtuin family of deacetylases is implicated in cellular pathways that influence longevity in yeast, C. elegans, Drosophila, and mammals (Tissenbaum and Guarente, 2001; Anderson et al., 2003; Howitz et al., 2003; Wood et al., 2004; Baur et al., 2006).”

“The sirtuin family of deacetylases is implicated in cellular pathways that influence longevity in yeast, C. elegans, Drosophila, and mammals (Tissenbaum and Guarente, 2001; Anderson et al., 2003; Howitz et al., 2003; Wood et al., 2004; Baur et al., 2006).”

“Sirtuins, specifically SirT2, can deacetylate -tubulin (North et al., 2003), the structural component of microtubules.”

“Mice were trained to criterion (escape latency 25 s) in the spatial reference version of the MWM to find the location of a hidden platform (Billings et al., 2005).”

“…in transgenic Drosophila and improve motor impairment and neuropathology in transgenic mouse models of both Huntington’s disease (HD) and spinal bulbar muscular atrophy (McCampbell et al., 2001; Steffan et al., 2001; Ferrante et al., 2003; Hockly et al., 2003; Minamiyama et al., 2004).”

“In addition to the polyglutamine repeat diseases, beneficial effects of HDAC inhibitors have been reported in animal models of Parkinson’s disease (PD), ALS, and experimental autoimmune encephalomyelitis (Gardian et al., 2004; Camelo et al., 2005; Ryu et al., 2005; Fischer et al., 2007).”

“Frederick Alt (Harvard University, Boston, MA) (Cheng et al., 2003).”

“…complements a number of emerging studies showing that Sir2 inhibitors improve pathology in other neurodegenerative diseases including Huntington’s disease and other models of polyglutamine repeat disorders (Ghosh and Feany, 2004; Pallos et al., 2008) and Parkinson’s disease (Outeiro et al., 2007).”

“…in transgenic Drosophila and improve motor impairment and neuropathology in transgenic mouse models of both Huntington’s disease (HD) and spinal bulbar muscular atrophy (McCampbell et al., 2001; Steffan et al., 2001; Ferrante et al., 2003; Hockly et al., 2003; Minamiyama et al., 2004).”

“An impact on microtubule stability would therefore be significant in AD as tau pathology leads to the breakdown of microtubules leading to impairments in neuronal transport (Alonso et al., 1997; Ebneth et al., 1998; Sengupta et al., 1998; Evans et al., 2000).”

“The sirtuin family of deacetylases is implicated in cellular pathways that influence longevity in yeast, C. elegans, Drosophila, and mammals (Tissenbaum and Guarente, 2001; Anderson et al., 2003; Howitz et al., 2003; Wood et al., 2004; Baur et al., 2006).”

“…in transgenic Drosophila and improve motor impairment and neuropathology in transgenic mouse models of both Huntington’s disease (HD) and spinal bulbar muscular atrophy (McCampbell et al., 2001; Steffan et al., 2001; Ferrante et al., 2003; Hockly et al., 2003; Minamiyama et al., 2004).”

“The activity of GSK3 can be inhibited by phosphorylation of serine 9 (Dajani et al., 2001), such that steady-state levels of this inactive GSK3 can be used to gauge overall activity.”

“Protein extracts were prepared from cells using a break buffer (50 mM NaH2PO4, 300 mM NaCl, 10 mM imidazole, 0.005% Tween 20 at pH 8.0 with the following inhibitors: 5 mM butyrate, 5 mM nicotinamide, phosphatase inhibitor cocktail I and II (Sigma-Aldrich), 1 mM PMSF, 0.001 mg/ml aprotinin and leupeptin, 20 mM N-ethylm…”

“An impact on microtubule stability would therefore be significant in AD as tau pathology leads to the breakdown of microtubules leading to impairments in neuronal transport (Alonso et al., 1997; Ebneth et al., 1998; Sengupta et al., 1998; Evans et al., 2000).”

“Nicotinamide prevents cognitive deficits in AD mouse model Nicotinamide, also known as niacinamide, is a sirtuin inhibitor and the biologically active form of niacin (vitamin B3) which has been widely used clinically for 40 years (Knip et al., 2000).”

“These impairments may be involved in the synaptic loss and subsequent retrograde degeneration (Terry, 1998; Mandelkow et al., 2003) characteristic of neurodegeneration in AD.”

“Nicotinamide was shown to markedly reduce Thr231-phosphotau levels; this particular species of tau has been reported to interfere with microtubule polymerization (Sengupta et al., 1998; Cho and Johnson, 2004), and is a commonly used biomarker for AD found in CSF (Ewers et al.”

“In addition to the polyglutamine repeat diseases, beneficial effects of HDAC inhibitors have been reported in animal models of Parkinson’s disease (PD), ALS, and experimental autoimmune encephalomyelitis (Gardian et al., 2004; Camelo et al., 2005; Ryu et al., 2005; Fischer et al., 2007).”

“Altered HAT and HDAC activities profoundly affect many critical cellular processes and are linked to several human diseases including cancer, fragile X syndrome, Rubinstein-Taybi syndrome, and neurodegenerative disorders (Timmermann et al., 2001).”

“3xTg-AD and NonTg mice (which included nicotinamide treated and untreated groups; n 8/group) were tested on the Morris water maze (MWM), a spatial task that is highly dependent on the hippocampus (Sutherland and McDonald, 1990).”

“In addition to the polyglutamine repeat diseases, beneficial effects of HDAC inhibitors have been reported in animal models of Parkinson’s disease (PD), ALS, and experimental autoimmune encephalomyelitis (Gardian et al., 2004; Camelo et al., 2005; Ryu et al., 2005; Fischer et al., 2007).”

“In another p25 transgenic mouse, transient overexpression of p25 improved hippocampus-dependent memory and facilitated long-term potentiation (Fischer et al., 2005).”

“…complements a number of emerging studies showing that Sir2 inhibitors improve pathology in other neurodegenerative diseases including Huntington’s disease and other models of polyglutamine repeat disorders (Ghosh and Feany, 2004; Pallos et al., 2008) and Parkinson’s disease (Outeiro et al., 2007).”

“…in transgenic Drosophila and improve motor impairment and neuropathology in transgenic mouse models of both Huntington’s disease (HD) and spinal bulbar muscular atrophy (McCampbell et al., 2001; Steffan et al., 2001; Ferrante et al., 2003; Hockly et al., 2003; Minamiyama et al., 2004).”

“…in transgenic Drosophila and improve motor impairment and neuropathology in transgenic mouse models of both Huntington’s disease (HD) and spinal bulbar muscular atrophy (McCampbell et al., 2001; Steffan et al., 2001; Ferrante et al., 2003; Hockly et al., 2003; Minamiyama et al., 2004).”

“Two major kinases, cyclin-dependent kinase 5 (cdk5) and GSK3 , have been shown to participate in the pathological hyperphosphorylation of tau in both the 3xTg-AD mice and in the human brain (Kobayashi et al., 1993; Flaherty et al., 2000).”

“Increased p35 to p25 cleavage is performed by calcium-dependent calpains, and interestingly recent data has shown calpain inhibitors to be protective in AD mouse models (Trinchese et al., 2008).”

“…have also been implicated in both apoptosis and necrosis; however we see no evidence for either of these with nicotinamide treatment, either with p53 levels (data not shown), or with other substrates of calpains such as MAP2 (Johnson et al., 1991), which is unchanged or increased with treatment.”

“Importantly, in AD brain acetylated -tubulin is decreased in tangle bearing neurons (Hempen and Brion, 1996), demonstrating the relationship between hyperphosphorylated tau, such as Thr231phosphotau, and breakdown of microtubules.”

“An impact on microtubule stability would therefore be significant in AD as tau pathology leads to the breakdown of microtubules leading to impairments in neuronal transport (Alonso et al., 1997; Ebneth et al., 1998; Sengupta et al., 1998; Evans et al., 2000).”

“Vehicletreated 3xTg-AD mice reached criterion in 6 d, in line with previous findings (Billings et al., 2007), whereas 3xTg-AD mice treated with nicotinamide required only 4 d (Fig.”

“, 1998; Cho and Johnson, 2004), and is a commonly used biomarker for AD in CSF (Ewers et al., 2007).”

“MAP2c is 80% homologous to tau within its microtubule binding domains (Roger et al., 2004), and the two proteins display similar microtubule binding affinity.”

“…complements a number of emerging studies showing that Sir2 inhibitors improve pathology in other neurodegenerative diseases including Huntington’s disease and other models of polyglutamine repeat disorders (Ghosh and Feany, 2004; Pallos et al., 2008) and Parkinson’s disease (Outeiro et al., 2007).”

“In addition to the polyglutamine repeat diseases, beneficial effects of HDAC inhibitors have been reported in animal models of Parkinson’s disease (PD), ALS, and experimental autoimmune encephalomyelitis (Gardian et al., 2004; Camelo et al., 2005; Ryu et al., 2005; Fischer et al., 2007).”

“Microtubules are composed of - and -tubulin dimers, and posttranslational modifications such as acetylation and detyrosination increase their stability (Cambray-Deakin and Burgoyne, 1987).”

“Similarly, p25 expression is associated with improved learning and memory through its role in upregulation of neuronal structural and synaptic proteins (Angelo et al., 2003; Fischer et al., 2005).”

“Phosphorylation of tau at Thr231 can occur via either of the major tau kinases, GSK3 or Cdk5, both of which show increasing activity with increasing age in either 3xTg-AD or nonTg mice, but no differences between the two genotypes at 8 months of age (Oddo et al., 2007).”

“These impairments may be involved in the synaptic loss and subsequent retrograde degeneration (Terry, 1998; Mandelkow et al., 2003) characteristic of neurodegeneration in AD.”

“Previous clinical trials with oral NADH have been performed and showed mixed results (Rainer et al., 2000; Demarin et al., 2004).”

“NAD+ accumulation may inhibit the phosphorylation of different Tau protein sites by inhibiting the activity of Cdk5-p25 complex.501 Nicotinamide, as a competitive inhibitor of sirtuins, specifically reduces the phosphorylation of tau (Thr231), which is related to microtubule depolymerization in an analogous manner to…”

“Others have reported that nicotinamide treatment restores cognitive performance in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and reduction of levels of hyperphosphorylated tau (194).”

“Based on the promising data from ADmice (Green et al., 2008), a phase II clinical trial of NAMon 15ADpatients withmild tomoderate dementia (1,500 mg twice daily) for 24 weeks was performed (NCT00580931) (Phelan et al., 2017).”