Many efforts to find a treatment for Alzheimer disease have focused on discovering a way to reduce Aβ, with largely disappointing results so far. Now the spotlight seems to be shifting to a greater interest in tau as a therapeutic target. Two new research papers help strengthen the case for the importance of this microtubule binding protein in AD. In the September 16 PLoS Genetics, researchers led by Alison Goate at Washington University in St. Louis, Missouri, reported the results of a screen in which they looked for gene variants associated with cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau). They found an allele in the protein phosphatase B gene that not only associates with high CSF p-tau, but also with a faster rate of progression of AD. This finding supports the idea that tau increases the severity of the disease, and implies that treatments targeting tau might delay disease progression. Meanwhile, in September 23 Neuron, a research group led by Li Gan at the University of California in San Francisco described a mechanism that blocks the clearance of hyperphosphorylated tau and may contribute to the accumulation of tau in neurofibrillary tangles. Tau can be acetylated, the authors report, and acetylation prevents the protein degradation machinery from chewing up tau and eliminating it from the cell. Modifying tau acetylation, therefore, could be another approach for reducing tau levels.

The Washington University group wanted to find additional genes that contribute to AD. Traditional gene hunting methods compare the genetics of cases and controls, but misdiagnosis and overlapping pathologies can lead to a lot of noise in the data. An alternative method is to look for genes that associate with an endophenotype, or an inherited phenotype linked to the disease. Endophenotypes have been used to find genes for conditions such as osteoporosis and heart disease, but they have not yet been widely employed in AD studies. The advantage of using endophenotypes, said first author Carlos Cruchaga, is that the grouping of samples is more objective and quantitative, and the method therefore provides more statistical power than case-control studies. In the September Journal of Alzheimer’s Disease, the authors report a validation of sorts for this approach. First author John Kauwe correlated levels of CSF Aβ and tau with known AD-associated genetic polymorphisms, hoping to glean clues about how the genes contribute to the disease. Kauwe and colleagues found a marginal association of the calcium homeostasis modulator 1 (CALHM1) gene with CSF Aβ42 levels, suggesting that the endophenotype screening approach might prove useful.

In the PLoS Genetics paper, Cruchaga and colleagues took this idea a step further, selecting for analysis 355 single nucleotide polymorphisms (SNPs) in 34 candidate genes believed to have roles in tau metabolism. Cruchaga and colleagues then looked for a connection between specific SNPs and the level of CSF tau phosphorylated at threonine 181 (p-tau181). For initial screening, the authors used 353 CSF samples from the WashU Alzheimer’s Disease Research Center, then they retested SNPs with significant associations in an independent series of 493 CSF samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the University of Washington, Seattle. Only one SNP, located in the regulatory subunit of the protein phosphatase B gene (also known as calcineurin B), was significant in both populations. People with either one or two copies of the less common allele had higher levels of CSF p-tau181 than those homozygous for the common allele of this SNP.

Cruchaga and colleagues followed this up by looking for a connection between this SNP and disease parameters such as risk, age of onset, and rate of progression. They found that people who carried the allele associated with higher CSF p-tau181 levels had a sixfold faster cognitive decline (as measured by the change in the clinical dementia rating per year) than those homozygous for the common allele. In brains with Aβ pathology, but not in normal brains, the harmful SNP was also associated with lower levels of protein phosphatase B mRNA, and with more neurofibrillary tangles.

Moving on from the candidate gene approach, the authors are now screening the whole genome for SNPs associated with CSF levels of tau and Aβ, Cruchaga said, and they hope to publish the results before the end of the year. They will again analyze any genes they find to see if they are linked to the risk of developing AD, the age of onset, or the rate of cognitive decline. “We think we will be able to find new genetic variants that are associated with different facets of AD,” Cruchaga said.

Finding that tau levels are connected to disease progression fits well with previous research, said Henrik Zetterberg at Brigham and Women’s Hospital, Boston, Massachusetts. Not only has tau been shown to act downstream of Aβ, with several experiments showing that cognition in mouse models can be improved by intervening at the level of tau (see ARF related news story on Santacruz et al., 2005; ARF related news story on Roberson et al., 2007; and ARF related news story on Ittner et al., 2010), but other studies have seen an association between high CSF tau levels and faster cognitive decline, as well as a higher mortality rate (see Sämgård et al., 2009 and Wallin et al., 2010). “The new thing, in this paper, is that there can actually be distinct genetic traits that determine how individuals might react to amyloid pathology,” Zetterberg said. “Some people can stand amyloid pathology better than others and [this paper is] unveiling the genetics behind that.” He suggested that in the future, researchers might be able to group people with AD according to their genetic traits, and perhaps prescribe medication on the basis of genetic makeup.

Stratifying patients into subgroups will be very important for effective treatment, agreed Khalid Iqbal at the New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York. “I think it’s very clear that AD is really a whole class of diseases,” he said, which will not all be amenable to a single treatment. Iqbal also applauds a focus on tau as a therapeutic target. “I think now there’s a recognition in the field that independent of whether the amyloid cascade hypothesis is true, you have to have neurofibrillary degeneration to produce the clinical phenotype.”

Iqbal points out, however, that association studies such as this one need to be verified by experimentation. In particular, he is puzzled by the finding that protein phosphatase B associates with levels of p-tau181, as most research to date demonstrates that tau dephosphorylation, particularly at threonine 181, is instead regulated by protein phosphatase A (see, e.g., Liu et al., 2005). “The previous evidence is not in favor of protein phosphatase B to be a significant player when it comes to the hyperphosphorylation of tau,” Iqbal said. He speculated that perhaps there is some indirect effect of protein phosphatase B. Cruchaga said, however, that their group’s findings do not imply that protein phosphatase A is not important, only that they didn’t find a genetic variant in PPA that modifies tau. Cruchaga added that they are in the process of experimentally validating their PPB findings.

The finding that high p-tau levels associate with decreased calcineurin levels also appears to contradict data from Brad Hyman’s lab at Massachusetts General Hospital, Charlestown, and Chris Norris’s at the University of Kentucky in Lexington. Both showed that Aβ leads to increased activation of calcineurin, promoting downstream effects that include misshapen neurons and loss of spines (see ARF related news story and ARF news story on Wu et al., 2010). This work implicates calcineurin as one of the culprits in the pathogenesis of AD. Cruchaga says that the contradictory data might be explained in part by local effects. Aβ promotes calcium influx, which activates calcineurin in the immediate area of dendritic spines, Cruchaga said. However, his group is now examining global calcineurin protein and activity levels in human AD brains, and has preliminary data that overall calcineurin activity decreases as dementia progresses.

There are also many other sites on tau that get phosphorylated, and the second paper focused on that aspect. Aggregations of hyperphosphorylated tau are a characteristic feature of both AD and frontotemporal dementia, but it is not clear what causes their accumulation. Li Gan and colleagues at UCSF hypothesized that the problem might be faulty clearance of tau by the protein degradation system. Proteins are normally marked for degradation by the addition of ubiquitin to lysine residues, but ubiquitination can be blocked if acetyl groups are first added. First author Sang-Won Min and colleagues began by demonstrating that tau can be acetylated by the histone acetyltransferase p300 in vitro. The researchers next generated antibodies specific for acetylated tau, and used them to look for the modified protein in vivo, finding that human tau gets acetylated in transgenic mice.

Using transfected cell cultures, conditional knockout mice, and various loss of function and gain of function mutants, the authors then showed that it is the sirtuin protein SIRT1 that deacetylates tau both in vitro and in vivo. SIRT1 and tau co-immunoprecipitate, suggesting that they directly interact. In cell cultures, inhibiting the deacetylase led to slower turnover of tau, supporting the idea that acetylation prevents tau degradation. In contrast, when p300 was inhibited in cultures, acetylated tau was eliminated, and within two hours pathogenic phosphorylated tau disappeared as well, hinting at the therapeutic potential of this approach.

Finally, Min and colleagues connected these findings more directly to AD by showing that Aβ treatment of primary neurons increases the level of acetylated tau, although the mechanism is unknown. Importantly, in postmortem cortices from patients with tau pathologies, the levels of acetylated tau peaked at later stages of the disease, agreeing with the idea that tau acetylation is linked to disease in human brains. However, acetylated tau appeared before the accumulation of hyperphosphorylated tau and neurofibrillary tangles, fitting with the idea that acetylation inhibits clearance.

The results suggest that reducing tau acetylation could be an alternative way to decrease levels of phosphorylated tau, Gan said. To investigate this, the authors will cross tauopathy mouse models with SIRT1 conditional knockouts and SIRT1 overexpressors, and look for changes in disease symptoms. Gan added that they don’t think SIRT1 is the only deacetylase for tau, but it is the one they have the strongest evidence for at the moment. A possible therapeutic approach to reduce tau would be to inhibit p300, the protein that acetylates tau, but because this acetylase has numerous other roles in the body, this would likely lead to side effects, Gan said. Instead, she speculated that further research might uncover more specific, appropriate therapeutic targets in the same pathway.

Several studies have shown that SIRT1 has a role in neuronal plasticity, learning and memory (see ARF related news story on Michán et al., 2010 and ARF related news story on Gao et al., 2010), although it is not known if SIRT1’s role in memory has anything to do with its deacetylase functions. The pathways could be completely separate, Gan said, but added that altogether, the data “certainly point to the emerging role of SIRT1 in neurons.” Intriguingly, SIRT1 levels are reduced in AD brains, and this parallels tau accumulation (see Julien et al., 2009), and the sirtuin has been found to be neuroprotective in AD (see ARF related news story on Kim et al., 2007), and to suppress β amyloid production (see ARF related news story on Donmez et al., 2010).

The tau acetylation findings are novel, said Li-Huei Tsai at MIT, and the data provide “another line of evidence suggesting that SIRT1 regulates multiple components of Alzheimer disease pathology. The fact that SIRT1 deacetylase has an enzyme-substrate relationship with tau is clearly intriguing.”

Leonard Guarente at MIT concurs. Guarente co-chairs the scientific advisory board for the pharmaceutical company GlaxoSmithKline, which bought Sirtris, a biotech company that develops drugs based on sirtuins. “I think it is fascinating that SIRT1 directly affects both Aβ and tau,” he wrote to ARF. “Brain permeable SIRT1 activators may really help mitigate AD because of the multiple beneficial effects.”—Madolyn Bowman Rogers


  1. This is a very interesting paper from Allison Goate and coworkers, who push genotype-phenotype analyses to the next level—towards understanding how variations in biomarkers relate to risk of progression of disease. A specific allele of calcineurin B, one of the subunits of calcineurin, is associated with rate of progression, phospho-tau levels, and tangle numbers. This is a tour de force of genotype-phenotype correlations and begins to potentially explore the wide variability in disease progression observed clinically. Of importance, age of onset travels not with calcineurin B, but with amyloid-related markers.

    Calcineurin activation has been implicated by Paul Greengard and colleagues, Roberto Malinow’s laboratory, as well as multiple others, as being critical for expression of amyloid-β synaptotoxicity. Recent data from our laboratory, and from Chris Norris and colleagues, demonstrated elevated calcineurin activity in neurons and in glia in AD models and in AD brain, in part due to post-translational changes that lead to a constitutively active form. How this relates to the new genetic findings, and to tau phosphorylation, is not yet clear—and raises new questions about how regulation of calcineurin at the mRNA level relates to activity in the AD brain. Nonetheless, the link of biochemical and genetic data both focusing on calcineurin pathways is intriguing, and serves to highlight the potential importance of this central signaling pathway in AD pathophysiology.

    View all comments by Bradley Hyman
  2. The debate continues about which key modifications turn tau into a neuron killer. This study by Min et al. provides support for an original hypothesis suggesting that acetylation of tau is a key event in its pathogenicity. Using two antibodies they have developed that are specific for acetylated tau, they confirm that tau is acetylated in cultured neuronal cells as well as in the brains of mouse AD models and AD patients. They provide compelling data indicating that acetylated tau is less prone to ubiquitination, thereby reducing its recycling and favoring its hyperphosphorylation. They then show that a deacetylase present in the brain, SIRT1, can effectively reduce the proportion of both acetylated and ser202-phosphorylated tau. Probably the most interesting aspect of their work is that they actually suggest that decreasing the acetylation of tau is a potential relevant therapeutic target for AD, and that activation of SIRT1 may actually do that.

    The connection between SIRT1 and AD has received much attention lately, suggesting that SIRT1 activation might represent a potential therapeutic target (Gan and Mucke, 2008; Guarente and Picard, 2005; Lavu et al., 2008). This was firstly based on the discovery that SIRT1 played a critical role in the beneficial effect of calorie restriction against aging processes (Gan and Mucke, 2008; Guarente and Picard, 2005). In vitro and in vivo evidence suggest that increased neuronal SIRT1 activity leads to attenuation of amyloid pathology through regulation of the serine/threonine kinase ROCK1 and elevated α-secretase activity (Qin et al., 2006a; Qin et al., 2006b; Donmez et al., 2010). The link with tau is more recent and also more controversial. In support of such a link, we have recently found that postmortem levels of SIRT1 were correlated with ante-mortem cognitive status and to the extent of tau neuropathology (Julien et al., 2009). However, data from LaFerla’s group show that SIRT1 genetic knockdown leads instead to reduced Thr231-phosphorylated tau (Green et al., 2008), in sharp contrast with data from Min et al.

    In summary, these exciting new data provide additional support for the development of brain-penetrant SIRT1 activators that are more potent and more selective than resveratrol (Feige et al., 2008; Lavu et al., 2008) or other tau-specific deacetylases.


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    View all comments by Frederic Calon
  3. This paper by Min et al. demonstrates that tau can be acetylated by the acetyltransferase p300/CBP, and that tau interacts with and is deacetylated by the Class III histone deacetylase Sirt1. The authors further show that after treatment of cells with MG132, which can inhibit the proteasome as well as lysosomal proteases (Lee and Goldberg 1998), levels of ubiquitinated tau increase with low doses of the Sirt1 inhibitor Ex527 (1μM), but are reduced on treatment with higher (10-50μM) doses of the sirtuin inhibitor (see Figure 6E). They demonstrate that in cell culture these higher doses of Ex527 reduce clearance of tau, which they propose is due to reduction in tau ubiquitination, and they show that tau acetylation is elevated under pathological conditions. Further, they inhibit p300/CBP pharmacologically and show a reduction in toxic phospho-tau. They logically conclude that activation of Sirt1 or inhibition of p300/CBP may be useful therapeutically in the treatment of tauopathy.

    Both the proteasome and the lysosome have been shown to degrade tau, and ubiquitin can target proteins for proteasomal as well as autophagic degradation (Wang, Martinez-Vicente et al. 2009; Korolchuk, Menzies et al. 2010). Clearance pathways can compensate for one another when one becomes impaired, and mechanisms of autophagic clearance in mammals are still being defined (Steffan 2010). Since multiple pathways of tau clearance exist, acetylation may activate tau clearance by one mechanism but reduce its clearance by another. We demonstrated that genetic reduction of Sirt1, or its pharmacologic inhibition with nicotinamide, can reduce phosphorylated tau levels in a triple transgenic mouse model of AD, and that nicotinamide treatment prevents cognitive deficits (Green, Steffan et al. 2008). Similarly, we found that phosphorylation/acetylation of Huntingtin (Htt), the protein mutated in Huntington’s Disease (HD), activates its clearance by the proteasome and lysosome–consistent with a previous observation by the laboratory of Dimitri Krainc that mutant Huntingtin acetylation regulates its clearance by macroautophagy (Jeong, Then et al. 2009; Thompson, Aiken et al. 2009).

    Recently, nicotinamide was shown to substantially improve motor deficits in a mouse model of HD (Hathorn, Snyder-Keller et al. 2010). The data described by Min et al. do suggest that activation of SIRT1 and inhibition of p300/CBP may increase a mechanism of clearance of tau. This does not preclude the possibility that increased acetylation induced by histone deacetylase inhibitors (class I, II and III) may activate a second mechanism of tau clearance which may be very important in brain (Steffan 2010). HDAC inhibition has been widely shown to be useful in the treatment of neurodegeneration (Mai, Rotili et al. 2009). Min et al. themselves show increased ubiquitination of tau with 1μM Ex527 treatment, consistent with that level of Sirt1 inhibition activating tau clearance in their system.

    While phosphorylated/acetylated tau may indeed be the toxic species in tauopathy, activation of the mechanism of modified tau clearance by inhibiting rather than activating Sirt1 early in disease progression has already been shown in vivo to be a successful therapeutic approach.


    . Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci. 2008 Nov 5;28(45):11500-10. PubMed.

    . Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington's disease. Neurobiol Dis. 2011 Jan;41(1):43-50. PubMed.

    . Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell. 2009 Apr 3;137(1):60-72. PubMed.

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    . Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron. 2010 Sep 23;67(6):953-66. PubMed.

    . Does Huntingtin play a role in selective macroautophagy?. Cell Cycle. 2010 Sep 1;9(17):3401-13. PubMed.

    . IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J Cell Biol. 2009 Dec 28;187(7):1083-99. PubMed.

    . Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet. 2009 Nov 1;18(21):4153-70. PubMed.

    View all comments by Joan Steffan
  4. This elegant manuscript by Cruchaga et al. reveals that CSF phospho-tau levels and the rate of disease progression in AD subjects are strongly correlated to the presence of SNPs in the regulatory B subunit of calcineurin, a Ca2+/calmodulin-dependent protein phosphatase implicated in several peripheral and neurologic disorders. These important observations could help establish a novel diagnostic marker in the clinic and lead to the development of treatments tailored to specific patient subpopulations.

    At the same time, caution may be warranted in regard to the functional impact of these SNPs on calcineurin function in AD. The authors suggest that calcineurin B SNPs “reduce calcineurin expression/activity leading to an increase in tau phosphorylation, tau pathology and neurodegeneration in individuals with Aβ deposition.” This conclusion was based on two primary pieces of evidence: First, that calcineurin inhibitors increase tau phosphorylation in mice (1,3) and second, that calcineurin activity is reduced in Alzheimer’s disease brain (4). However, numerous recent findings seem inconsistent with a “reduced calcineurin” hypothesis. In particular, calcineurin inhibitors (or inhibitors of the calcineurin-dependent transcription factor NFAT) typically provide strong protection against synaptic dysfunction (5,6), dendritic atrophy/spine retraction (7-9), neuroinflammation (10,11), amyloid pathology (12,13), neuronal death (14,15), and cognitive decline (16) in a variety of cell culture and/or animal models of AD.

    Moreover, recent studies using alternative antibodies and assays have observed hyperactive, rather than hypoactive, calcineurin signaling in AD mice and in subjects with MCI or AD (8,16-19). The work performed on postmortem human tissue suggests that AD-mediated changes in calcineurin signaling are very complex and depend on a number of factors including: the brain region, cell type (neurons vs glia), and calcineurin isoform (alpha vs beta) investigated; the proteolytic state and subcellular localization of the calcineurin catalytic subunit (i.e. the A subunit); and the pathologic and cognitive status of the subject. Clearly, it will be important to determine how SNPs in the regulatory calcineurin B subunit affect these calcineurin A signaling properties.


    . Inhibition of calcineurin by infusion of CsA causes hyperphosphorylation of tau and is accompanied by abnormal behavior in mice. Biol Chem. 2006 Jul;387(7):977-83. PubMed.

    . Infusion of FK506, a specific inhibitor of calcineurin, induces potent tau hyperphosphorylation in mouse brain. Brain Res Bull. 2008 Jul 30;76(5):464-8. PubMed.

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    . Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci. 2007 Mar 14;27(11):2866-75. PubMed.

    . Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci. 2010 Feb 17;30(7):2636-49. PubMed.

    . Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron. 2008 Jul 31;59(2):214-25. PubMed.

    . Interleukin-1beta-dependent signaling between astrocytes and neurons depends critically on astrocytic calcineurin/NFAT activity. J Biol Chem. 2008 Aug 8;283(32):21953-64. Epub 2008 Jun 9 PubMed.

    . Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007 Feb 1;53(3):337-51. PubMed.

    . Disrupted intracellular calcium regulates BACE1 gene expression via nuclear factor of activated T cells 1 (NFAT 1) signaling. Aging Cell. 2008 Mar;7(2):137-47. PubMed.

    . RAGE regulates BACE1 and Abeta generation via NFAT1 activation in Alzheimer's disease animal model. FASEB J. 2009 Aug;23(8):2639-49. PubMed.

    . Overactivation of calcineurin induced by amyloid-beta and prion proteins. Neurochem Int. 2008 May;52(6):1226-33. PubMed.

    . Selective induction of calcineurin activity and signaling by oligomeric amyloid beta. Aging Cell. 2008 Dec;7(6):824-35. PubMed.

    . Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice. Neurobiol Learn Mem. 2007 Sep;88(2):217-24. PubMed.

    . Cognitive decline in Alzheimer's disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci. 2009 Oct 14;29(41):12957-69. PubMed.

    . Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. J Biol Chem. 2005 Nov 11;280(45):37755-62. PubMed.

    . Calcineurin triggers reactive/inflammatory processes in astrocytes and is upregulated in aging and Alzheimer's models. J Neurosci. 2005 May 4;25(18):4649-58. PubMed.

    View all comments by Chris Norris

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News Citations

  1. No Toxicity in Tau’s Tangles?
  2. APP Mice: Losing Tau Solves Their Memory Problems
  3. Honolulu: The Missing Link? Tau Mediates Aβ Toxicity at Synapse
  4. Chicago: NFATs, Calcineurin—Mediators of AD, PD Pathogenesis?
  5. Calcium Hypothesis—Studies Beef Up NFAT, CaN, Astrocyte Connections
  6. Research Brief: SIRTs Keep Brain Minty Fresh
  7. Mechanisms and Memory: The Choreography of CREB, the Balance of BDNF
  8. Overworked HDACs Leave Transcriptional Posts to Push DNA Repair

Paper Citations

  1. . Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005 Jul 15;309(5733):476-81. PubMed.
  2. . Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science. 2007 May 4;316(5825):750-4. PubMed.
  3. . Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell. 2010 Aug 6;142(3):387-97. Epub 2010 Jul 22 PubMed.
  4. . Cerebrospinal fluid total tau as a marker of Alzheimer's disease intensity. Int J Geriatr Psychiatry. 2010 Apr;25(4):403-10. PubMed.
  5. . CSF biomarkers predict a more malignant outcome in Alzheimer disease. Neurology. 2010 May 11;74(19):1531-7. PubMed.
  6. . Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci. 2005 Oct;22(8):1942-50. PubMed.
  7. . Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci. 2010 Feb 17;30(7):2636-49. PubMed.
  8. . SIRT1 is essential for normal cognitive function and synaptic plasticity. J Neurosci. 2010 Jul 21;30(29):9695-707. PubMed.
  9. . A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature. 2010 Aug 26;466(7310):1105-9. PubMed.
  10. . Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol. 2009 Jan;68(1):48-58. PubMed.
  11. . SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 2007 Jul 11;26(13):3169-79. PubMed.
  12. . SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell. 2010 Jul 23;142(2):320-32. PubMed. RETRACTED

Further Reading

Primary Papers

  1. . SNPs associated with cerebrospinal fluid phospho-tau levels influence rate of decline in Alzheimer's disease. PLoS Genet. 2010 Sep;6(9) PubMed.
  2. . Validating predicted biological effects of Alzheimer's disease associated SNPs using CSF biomarker levels. J Alzheimers Dis. 2010;21(3):833-42. PubMed.
  3. . Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron. 2010 Sep 23;67(6):953-66. PubMed.