Could Longevity Factor, Epilepsy Med, Treat AD One Day?

Series - Gladstone Workshop: From Science to Therapeutics: The Best Way Forward:

At a San Francisco conference addressing Alzheimer’s and related disorders, the agenda featured a diverse mix of topics—occasionally even from the same lab. Lennart Mucke of the Gladstone Institute of Neurological Disease, which hosted the meeting 15-17 April 2013, discussed two fundamentally different treatment strategies—searching for new compounds and repurposing existing drugs. “We likely need to attack AD, like other multifactorial diseases, with a variety of different compounds,” said Mucke. Other speakers also pushed for a multipronged approach. Some discussed ways to improve the predictive power of experimental models and proposed strategies to nurture academic-industrial partnerships to speed drug discovery.

Mucke’s screening approach centers around Klotho, an anti-aging factor named after the Greek goddess who spins the thread of life (Kuro-O et al., 1997). In people, Klotho gene variants modulate longevity, though researchers are unsure how. When overexpressed in mice, Klotho extends their lifespan, possibly by suppressing insulin signaling and oxidative stress. The kidney expresses high levels of Klotho, which binds to ion channels and regulates their assembly. The brain’s choroid plexus also churns out a lot of this protein. “We know next to nothing about Klotho’s function in the nervous system,” Mucke said. Research in Carmela Abraham’s lab at Boston University indicates that Klotho expression falls not only with normal aging in monkey, rat, and mouse brain, but also in the brains of AD mice and people with AD (see ARF related conference story; see also ARF related news story).

To determine if systemic Klotho overexpression could treat mouse models of AD, Mucke and colleagues crossed Klotho transgenic mice (Kurosu et al., 2005) with his J20 line that expresses mutant human amyloid precursor protein (APP). APP/Klotho mice lived longer and did better in tests of spatial learning and memory than J20 controls, Mucke said at the meeting. “Of all genetic manipulations in our APP mice, this was one of the most striking phenotypes,” he said, noting that Klotho overexpression improved cognition in non-APP animals, too. Electrophysiology and pharmacology studies in the double transgenics yielded preliminary evidence that Klotho might exert these behavioral benefits through changes in particular neurotransmitter receptor levels.

Emerging human data support these results from mice, said Mucke. Together with Dena Dubal, Bruce Miller, and other colleagues at UCSF, Mucke examined data obtained in more than 700 seniors from three independent cohorts at the University of California, San Francisco; Rush University Medical Center in Chicago, Illinois; and the University of California, Los Angeles. In their analyses thus far, people with higher serum levels of Klotho had better cognition, Mucke told meeting attendees. The Klotho benefit did not depend on apolipoprotein E status. “We looked carefully at this and were surprised to find no interaction between Klotho and ApoE4,” he said.

Collectively, the data suggest that “augmenting Klotho could counteract the development of AD and related diseases of aging,” Mucke said. Since they see some effects in younger mice, he noted that Klotho may work through mechanisms that do not modulate the aging process per se. Abraham’s lab is screening novel compounds that boost Klotho expression (King et al., 2012), and Mucke is collaborating with her group to test potential candidates in mice. Other therapeutic approaches could include blocking Klotho turnover, stimulating its activities, activating downstream mediators, or quelling counteracting pathways.

In the second part of his talk, Mucke pivoted to a completely different strategy that he hopes will pay dividends more quickly. The anti-epilepsy drug levetiracetam suppressed seizures and improved performance in tests of behavior and cognition in J20 mice through a mechanism involving binding to the synaptic vesicle component SV2A (see ARF related news story on Sanchez et al., 2012). AD patients are prone to spontaneous seizures (Imfeld et al., 2012; Scharfman, 2012), and growing evidence from various labs supports a connection between AD and epilepsy (see ARF related conference story). As reported recently by Michela Gallagher of Johns Hopkins University, Baltimore, Maryland, levetiracetam quieted hippocampal activity and improved memory in a small sample of people with amnestic mild cognitive impairment (aMCI) (see ARF related news story on Bakker et al., 2012).

Mucke noted that cognitive improvements occurred in both mice and humans at similar plasma levels of levetiracetam. Mucke and Gallagher hope to test this drug in a Phase 2 AD trial but have not designed it yet. In working toward a next trial, they are weighing many considerations. For instance, is the drug effective only in people who actually have epileptiform activity, meaning enrollment would have to ascertain that? Is it effective only in certain disease stages or subtypes? Should other SV2A-binding molecules be tested?

In the meantime, Mucke and UCSF colleague Keith Vossel are enrolling people with AD, MCI, and other diseases including dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) into a clinical observational study to determine if they have epileptiform activity. At the research hospital, participants undergo a 36-hour electroencephalography (EEG) test as well as magnetoencephalography (MEG), another high-resolution measure of human brain activity. So far, the scientists have results for four MCI and 17 AD patients, as well as 11 controls. Almost half the AD patients had non-convulsive epileptiform activity, Mucke reported.—Esther Landhuis.

This is Part 3 of a three-part series. Part 1, Part 2. Read a PDF of the entire series.

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References

News Citations

  1. San Diego: Klotho Spins Threads Linking Aging and AD Research
  2. Barcelona: A Fistful of Schemes for Tackling Alzheimer’s
  3. Anticonvulsants Reverse AD-like Symptoms in Transgenic Mice
  4. Chicago: AD and Epilepsy—Joined at the Synapse?
  5. Epilepsy Drug Calms the Hippocampus, Aids Memory
  6. Therapeutic Approaches Target Deubiquitinase, Protein Turnover
  7. Paracrine Signal From BACE1-Clipped Neuregulin Rescues Myelin

Paper Citations

  1. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997 Nov 6;390(6655):45-51. PubMed.
  2. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-O M. Suppression of aging in mice by the hormone Klotho. Science. 2005 Sep 16;309(5742):1829-33. PubMed.
  3. King GD, Chen C, Huang MM, Zeldich E, Brazee PL, Schuman ER, Robin M, Cuny GD, Glicksman MA, Abraham CR. Identification of novel small molecules that elevate Klotho expression. Biochem J. 2012 Jan 1;441(1):453-61. PubMed.
  4. Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):E2895-903. PubMed.
  5. Imfeld P, Bodmer M, Schuerch M, Jick SS, Meier CR. Seizures in patients with Alzheimer's disease or vascular dementia: A population-based nested case-control analysis. Epilepsia. 2012 Dec 6; PubMed.
  6. Scharfman HE. "Untangling" Alzheimer's disease and epilepsy. Epilepsy Curr. 2012 Sep;12(5):178-83. PubMed.
  7. Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, Yassa MA, Bassett SS, Shelton AL, Gallagher M. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012 May 10;74(3):467-74. PubMed.

Other Citations

  1. J20 line

Further Reading

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