26 Jun 2015

In the June 25 Cell Metabolism, researchers led by Kalipada Pahan, Rush University Medical Center, Chicago, report that statins activate a novel pathway that raises levels of two neurotrophins in the brain. The findings could reinvigorate the long-standing debate about whether statins may make good therapeutics for neurodegenerative diseases.

“This group really nailed down a novel mechanism of action of statins,” said Elizabeth Head, University of Kentucky. “It is exciting to consider that neurotrophins could be upregulated in brain through a drug, which has not been feasible in the past.”

Statins, widely used to treat heart disease, are competitive inhibitors of HMG-CoA reductase, an enzyme that dictates the pace of cholesterol synthesis in the liver. By disrupting the pathway of cholesterol synthesis, which affects a number of intermediate signaling molecules (see image below), statins also have a host of pleiotropic effects. They reduce inflammation, encourage vasodilation, and reduce the production of reactive oxygen species (for a review, see Pahan, 2006).

Finding a New Path: In addition to the known pathway of cholesterol synthesis (right), statins influence levels of neurotrophins in the brain. [Courtesy of Roy et al., Cell Metabolism.]

Studies in mice suggest that statins could also improve cognitive function, learning, and memory, and reduce Alzheimer’s pathology (Kurata et al., 2011; Li et al., 2006). Epidemiological evidence in people backs that up—statins appear to lower the risk of Alzheimer’s disease and dementia (Wolozin et al., 2000; July 2007 news). However, prospective studies have failed to show that statins either reduce dementia risk or treat AD (Rea et al., 2005; Sano et al., 2011; Feldman et al., 2010). If there is a cognitive benefit, what could explain it? Pahan and colleagues wondered if statins influence the production of neurotrophins in the brain.

First author Avik Roy and colleagues treated separate cultures of mouse astrocytes, microglia, and cortical neurons with various statins. In all three types of cells, both the mRNA and protein levels rose for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). The same held true in both primary human astrocytes and neurons. In vivo, the scenario looked similar. Mice fed with simvastatin—the statin that most easily crosses the blood-brain barrier—produced more BDNF than normal in astrocytes, microglia, and cortical neurons, according to postmortem immunohistochemistry.

Surprisingly, this effect did not seem to depend on inhibition of HMG-CoA reductase. When the researchers pretreated cultured cells with mevalonate or farnesyl pyrophosphate, downstream products of the enzyme, neurotrophin levels still climbed upon administering simvastatin. This implied that statins rev production of neurotrophins a different way.

Upon closer inspection, the authors discovered that the drugs stimulated a nuclear transcription factor involved in fat metabolism, PPARα. Simvastatin only upregulated neurotrophins in vitro and in vivo in mice when PPARα was present, not when it was genetically knocked out. Various molecular methods confirmed that statins bound directly to the transcription factor, and that simvastatin had the strongest affinity.

However, there was a catch. PPARα does not directly promote production of neurotrophins. How are they connected, then? Roy and colleagues looked to known BDNF promoters, such as cAMP-response element binding protein (CREB). Knocking down CREB prevented statins from raising neurotrophin levels in astrocytes from mice. CREB also rose in mice fed simvastatin, but not if the animals lacked PPARα. The work suggests that statins modulate PPARα and CREB independently of HMG-CoA inhibition (see image).

To find out if this rise in neurotrophic factors imparted a behavioral benefit, Roy and colleagues examined hippocampus-dependent learning and memory in mice. In wild-type mice with intact PPARα, two weeks of daily simvastatin treatment raised BDNF expression in the cortex, and reduced errors in the Barnes navigation maze. The drug also improved memory in 5-month old 5xFAD mice, which have rampant amyloid plaques and poor memory, so long as PPARα was present.

“This paper provides a novel mechanism of how statins might act independently of the cholesterol pathway,” said Jochen Walter, University of Bonn, Germany. “That there is a direct interaction of statins with a transcriptional regulator is pretty surprising.”

Head and Walter agreed that this study might help explain why people who start taking statins in middle age have a lower incidence of Alzheimer’s (for a review, see Swiger et al., 2013). Scientists might also look at autopsy tissue from people who took statins to see if the same mechanism is at play, Head said. However, she cautioned that people who take statins have high cholesterol, and healthy people could react differently. The mice Roy and colleagues used ate normal mouse chow and had normal cholesterol levels.

Head noted that the statin doses given to mice in this study were comparable to those prescribed for people, making the finding all the more promising. Given that people take statins for long periods, both Head and Carl Cotman, University of California, Irvine, wondered how mice would have fared on more than two weeks of treatment.

How does this new data reconcile with inconclusive cognitive outcomes in statin trials? Walter said a number of factors could influence those studies, including when treatment begins relative to disease onset, the length of treatment, the types of assessment used, and the permeability of the statin to the blood-brain barrier.

To complicate matters, some studies have reported a decline in memory associated with statin use in elderly people (Wagstaff et al., 2003; Mandas et al., 2014). In the June 8 JAMA Internal Medicine, authors led by Warren Bilker, University of Pennsylvania Perelman School of Medicine, Philadelphia, suggest possible reasons. In a retrospective cohort study, they compared 483,000 statin users to a matched group taking no lipid-lowering drugs and 26,000 people taking non-statin versions. They found that all lipid-lowering drugs were equally associated with memory loss in the first month of use. While it’s still possible that this entire heterogeneous drug class causes memory decline, they argue that the association more likely resulted from detection bias. In other words, people taking the drugs make more visits to their physicians, who are then more likely to pick up on memory problems.—Gwyneth Dickey Zakaib

Comments

- Gary Landreth
  Indiana University School of Medicine
- Posted: 19 Jul 2015
This recent publication by Roy et al. reports a novel, non-canonical action of statins in the brain, whereby they stimulate the nuclear receptor PPARα. There has been considerable controversy over the pleiotrophic actions of the statins, in particular as they relate to Alzheimer’s disease. There is reasonable epidemiological evidence demonstrating a reduction in AD risk with sustained statin use. There was no clear linkage of these finding to suppression of cholesterol levels in the central nervous system. Clinical trials of statins, either in therapeutic or preventive AD trials, have failed. This manuscript brings together several disparate threads of research and potentially adds some clarity to the actions of the statins in the brain.

Importantly, Roy and colleagues have clearly established that stains bind to and activate the nuclear receptor PPARα in multiple cell types in the brain. Interestingly, the statins bind PPARαthrough interactions within the ligand-binding domain that differ from those employed by highly specific, synthetic PPARα agonists. There have been numerous reports of statins interacting with all PPARs, most frequently PPARγ. Here, the authors nicely demonstrate statin specificity for PPARα. The dissection of these interactions is impressive. However, there are several unanswered questions. For example, it is entirely unclear if statins drive the expression of canonical PPARα-regulated genes, and this would seem to be an important positive control bolstering their conclusion that statins act to activate PPARα.

Statins previously have been reported to induce the expression of neurotrophins, and the present study adds mechanistic clarity to this phenomenon. A striking finding is that induction of neurotrophin expression relies upon PPARa-driven CREB expression. These data nicely sync with their previous work. They report a PPAR response element (PPRE) in the promoter of the CREB gene, however, there are several consensus PPRE sequences that are specific for the individual PPAR receptors and it is unclear if the sequence they found conforms to that of PPARα.

Despite extensive investigation of statin actions in murine models of AD, there has been little support for their attenuation of disease pathogenesis in such models, particularly when it comes to improving behavior. Here, the authors report a significant improvement in spatial memory in statin-treated 5XFAD mice using the Barnes maze. This is not a typical test in this transgenic line, but the data are persuasive.

In summary, this is an important contribution to understanding the breadth of statin actions in the brain, with clear therapeutic implications.

View all comments by Gary Landreth

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References

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Pahan K. Lipid-lowering drugs. Cell Mol Life Sci. 2006 May;63(10):1165-78. PubMed.
Kurata T, Miyazaki K, Kozuki M, Panin VL, Morimoto N, Ohta Y, Nagai M, Ikeda Y, Matsuura T, Abe K. Atorvastatin and pitavastatin improve cognitive function and reduce senile plaque and phosphorylated tau in aged APP mice. Brain Res. 2011 Jan 31;1371:161-70. PubMed.
Li L, Cao D, Kim H, Lester R, Fukuchi K. Simvastatin enhances learning and memory independent of amyloid load in mice. Ann Neurol. 2006 Dec;60(6):729-39. PubMed.
Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000 Oct;57(10):1439-43. PubMed.
Rea TD, Breitner JC, Psaty BM, Fitzpatrick AL, Lopez OL, Newman AB, Hazzard WR, Zandi PP, Burke GL, Lyketsos CG, Bernick C, Kuller LH. Statin use and the risk of incident dementia: the Cardiovascular Health Study. Arch Neurol. 2005 Jul;62(7):1047-51. PubMed.
Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, Aisen PS. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011 Aug 9;77(6):556-63. PubMed.
Feldman HH, Doody RS, Kivipelto M, Sparks DL, Waters DD, Jones RW, Schwam E, Schindler R, Hey-Hadavi J, DeMicco DA, Breazna A, . Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2010 Mar 23;74(12):956-64. PubMed.
Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc. 2013 Nov;88(11):1213-21. Epub 2013 Oct 1 PubMed.
Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM. Statin-associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy. 2003 Jul;23(7):871-80. PubMed.
Mandas A, Congiu MG, Abete C, Dessi S, Manconi PE, Musio M, Columbu S, Racugno W. Cognitive decline and depressive symptoms in late-life are associated with statin use: evidence from a population-based study of Sardinian old people living in their own home. Neurol Res. 2014 Mar;36(3):247-54. PubMed.

Statins Boost Growth Factors in Mouse Brain, Improve Memory

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