25 Jul 2010

The sirtuin protein SIRT1 is emerging as an important player in learning and memory, and may have potential as a therapeutic target in Alzheimer disease. Fresh on the heels of a July 11 Nature paper that demonstrated a crucial role for SIRT1 in memory (see ARF related news story on Gao et al., 2010), two new papers add to the growing body of evidence that SIRT1 helps keep brains healthy. In a paper appearing July 21 in the Journal of Neuroscience, researchers led by Valter Longo at the University of Southern California, Los Angeles, show that a SIRT1 knockout mouse has numerous defects in learning and memory. This finding implies that SIRT1 could have a protective role in AD, and indeed, in a July 23 Cell paper, researchers led by Leonard Guarente at the Massachusetts Institute of Technology, Cambridge, report that overexpression of SIRT1 can decrease Aβ production and the number of amyloid plaques in a mouse model of AD.

SIRT1, a NAD-dependent deacetylase, is known to regulate numerous biological processes and to affect longevity. Longo and colleagues wanted to investigate what role the enzyme might play in normal brains. First author Shaday Michán confirmed that SIRT1 is highly expressed in neurons of the hippocampus, including in CA1, CA3, and the dentate gyrus, all regions important for memory. Michán and colleagues then investigated the functional role of SIRT1 by analyzing a SIRT1 knockout mouse line. The SIRT1 KOs demonstrated poorer immediate memory, associative memory (as seen in classical conditioning paradigms), and spatial learning. Although basal synaptic transmission was normal in the KOs, long-term potentiation (LTP) was impaired. The SIRT1 KOs also showed subtle structural defects. The structure of dendritic spines in CA1 was normal, but the granule cells in the dentate gyrus had smaller dendritic arbors, with fewer and shorter branches.

The authors have previously shown that phosphorylation of extracellular signal-regulated kinase 1 (ERK1) is decreased in the SIRT1 KO mouse (see ARF related news story on Li et al., 2008), while other researchers have shown that SIRT1 KOs have decreased levels of insulin-like growth factor 1 (IGF-1) (see Lemieux et al., 2005). Michán and colleagues looked for changes in hippocampal gene expression in the SIRT1 KOs using microarrays. The changes were small, but included genes regulated by ERK1/2 and IGF-1, as well as other genes involved in synaptic function and metabolism.

The next step, Longo said, will be to search for the mechanism behind SIRT1’s effects by seeing if an increase in IGF-1, for example, can reverse the learning disabilities of the KO mice. Longo suggested that the effects seen in the KO mouse might not be reversible through a single signaling pathway such as IGF-1, however, as SIRT1 is a regulatory protein that seems to coordinate numerous metabolic pathways. “It’s not clear yet whether these defects [in the SIRT1 KO] are in fact primarily in learning and memory, or primarily in these metabolic pathways that are so important for learning and memory.”

Michán and colleagues also examined a transgenic mouse that overexpressed SIRT1 16-fold in the brain. On this normal mouse background, the authors found that this massive SIRT1 overexpression conferred no improvements in learning or memory, and that synaptic function was unchanged except for a slight increase in neuronal excitability.

The second paper, by Guarente and colleagues, describes work first reported at the Keystone Symposium held 10-15 Jan at Copper Mountain, Colorado (see ARF related news story for full report). First author Gizem Donmez crossed a mouse that had a mild twofold overexpression of SIRT1 in the brain with an AD mouse model that expressed APP and PS1 (APPSwe/PS1ΔE9), and discovered that SIRT1 can protect against AD, lowering the production of Aβ and the number of plaques. The authors also crossed the AD mouse with a mouse that had a brain-specific conditional KO of SIRT1, and saw that Aβ and plaques increased.

These scientists found that SIRT1 increases levels of ADAM10, the α-secretase responsible for alternate cleavage of APP. In part, SIRT1 does this by coactivating the retinoic acid receptor β. Activation of α-secretase also led to increased cleavage of the Notch receptor; the Notch intracellular domain is known to activate genes for neurogenesis. Guarente and colleagues suggest, therefore, that SIRT1 may protect against AD by decreasing Aβ production and by increasing neurogenesis.

“SIRT1 does seem to be broadly protective in neurodegeneration,” David Sinclair of Harvard Medical School, a coauthor on the J Neurosci paper, wrote in an e-mail to ARF, “so brain-penetrant activators of SIRT1 could be a potential way to prevent and possibly treat AD.”—Madolyn Bowman Rogers

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References

News Citations

1. Mechanisms and Memory: The Choreography of CREB, the Balance of BDNF 16 Jul 2010
2. SIRT1, Resveratrol and More: Moving Closer to Anti-aging Elixir? 8 Jul 2008
3. Copper Mountain: Knight Vision—SIRT1 Aids ADAM10, Slays Aβ 1 Feb 2010

Paper Citations

1. Gao J, Wang WY, Mao YW, Gräff J, Guan JS, Pan L, Mak G, Kim D, Su SC, Tsai LH. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature. 2010 Aug 26;466(7310):1105-9. PubMed.
2. Li Y, Xu W, McBurney MW, Longo VD. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab. 2008 Jul;8(1):38-48. PubMed.
3. Lemieux ME, Yang X, Jardine K, He X, Jacobsen KX, Staines WA, Harper ME, McBurney MW. The Sirt1 deacetylase modulates the insulin-like growth factor signaling pathway in mammals. Mech Ageing Dev. 2005 Oct;126(10):1097-105. PubMed.

Further Reading

News

1. Mechanisms and Memory: The Choreography of CREB, the Balance of BDNF 16 Jul 2010
2. SIRT1, Resveratrol and More: Moving Closer to Anti-aging Elixir? 8 Jul 2008
3. Copper Mountain: Knight Vision—SIRT1 Aids ADAM10, Slays Aβ 1 Feb 2010