Drug Restores Cells and Memories in Alzheimer’s: Mouse Study

Summary: A new drug has proven effective at restoring memories and neural connections in mouse models of Alzheimer’s disease. The new drug was originally developed as a treatment for Schizophrenia. While the drug does not destroy amyloid plaques associated with Alzheimer’s, it does allow the plaques to co-exist with neurons.

Source: Yale.

A new drug can restore memories and connections between brain cells in mice with a model of Alzheimer’s disease, a new Yale-led study suggests.

“The drug completely erased evidence of Alzheimer’s synapse damage and memory loss in mouse models of the disease,” said Stephen Strittmatter, the Vincent Coates Professor of Neurology and senior author of the study appearing July 5 in the journal Cell Reports.

Researchers such as Strittmatter have made significant inroads into understanding the biology of Alzheimer’s disease, but identifying effective and safe treatments has been difficult. It is known that amyloid-beta peptides, the hallmark of Alzheimer’s, couple with prion protein at the surface of brain cells and transmit damaging instructions to the interior of the cell. Yale researchers had previously identified a protein on the cell membrane — metabotropic glutamate receptor 5 or mGluR5 — as the gateway that helps transmit damage from the coupling.

Previous attempts had been made to target mGluR5, but most drugs also disrupt signaling of glutamate, the most common neurotransmitter in the human brain. The new compound, Silent Allosteric Modulation or SAM (BMS 984923), was created by Bristol Myers Squibb as part of its effort to treat schizophrenia. The drug does not restrict neurotransmitter signaling in culture tissue or living mice, the study found. After four weeks of treatment, memory and synapses linking brain cells had been restored in mice with a model of Alzheimer’s.

“The drug does not destroy plaques associated with Alzheimer’s, but allows them to co-exist with neurons,” Strittmatter said.

Image shows cortical tissue.
Cortical tissue with plaques stained in blue, and astrocytes responding to drug treatment in red. NeuroscienceNews.com image is credited to the researchers.

Yale researchers say the next step is to prepare for preliminary trials of the drug’s effects on humans.

Primary funding for the research comes from the National Institutes of Health.

About this neuroscience research article

Yale’s Laura T. Haas is lead author of the study. Researchers from Bristol-Myers Squibb Research and Development also contributed to the paper.

Source: Bill Hathaway – Yale
Image Source: NeuroscienceNews.com image is credited to the researchers.
Original Research: Full open access research for “Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes” by Laura T. Haas, Santiago V. Salazar, Levi M. Smith, Helen R. Zhao, Timothy O. Cox, Charlotte S. Herber, Andrew P. Degnan, Anand Balakrishnan, John E. Macor, Charles F. Albright, and Stephen M. Strittmatter in Cell Reports. Published online July 5 2017 doi:10.1016/j.celrep.2017.06.023

Cite This NeuroscienceNews.com Article

[cbtabs][cbtab title=”MLA”]Yale “Drug Restores Cells and Memories in Alzheimer’s: Mouse Study.” NeuroscienceNews. NeuroscienceNews, 6 July 2017.
<https://neurosciencenews.com/pharmacology-memory-alzheimers-7041/>.[/cbtab][cbtab title=”APA”]Yale (2017, July 6). Drug Restores Cells and Memories in Alzheimer’s: Mouse Study. NeuroscienceNew. Retrieved July 6, 2017 from https://neurosciencenews.com/pharmacology-memory-alzheimers-7041/[/cbtab][cbtab title=”Chicago”]Yale “Drug Restores Cells and Memories in Alzheimer’s: Mouse Study.” https://neurosciencenews.com/pharmacology-memory-alzheimers-7041/ (accessed July 6, 2017).[/cbtab][/cbtabs]


Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes

•A potent mGluR5 SAM blocks Aβo/PrPC but not glutamate signaling
•The mGluR5 SAM rescues age-dependent memory loss in an AD mouse model
•Synapse density is restored by mGluR5 SAM treatment over 4 weeks
•mGluR5 SAM reveals a glutamate-independent AD role with a wide therapeutic index

Metabotropic glutamate receptor 5 (mGluR5) has been implicated in Alzheimer’s disease (AD) pathology. We sought to understand whether mGluR5’s role in AD requires glutamate signaling. We used a potent mGluR5 silent allosteric modulator (SAM, BMS-984923) to separate its well-known physiological role in glutamate signaling from a pathological role in mediating amyloid-β oligomer (Aβo) action. Binding of the SAM to mGluR5 does not change glutamate signaling but strongly reduces mGluR5 interaction with cellular prion protein (PrPC) bound to Aβo. The SAM compound prevents Aβo-induced signal transduction in brain slices and in an AD transgenic mouse model, the APPswe/PS1ΔE9 strain. Critically, 4 weeks of SAM treatment rescues memory deficits and synaptic depletion in the APPswe/PS1ΔE9 transgenic mouse brain. Our data show that mGluR5’s role in Aβo-dependent AD phenotypes is separate from its role in glutamate signaling and silent allosteric modulation of mGluR5 has promise as a disease-modifying AD intervention with a broad therapeutic window.

“Diffusion tensor MRI tractography reveals increased fractional anisotropy (FA) in arcuate fasciculus following music-cued motor training” by Emma Moore, Rebecca S. Schaefer, Mark E. Bastin, Neil Roberts, and Katie Overy in Brain & Cognition. Published online June 12 2017 doi:10.1016/j.bandc.2017.05.001

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