Neuregulin-1 Identified As Potential Alzheimer's Disease Treatment

Overexpression of either type I or type III neuregulin-1 (Nrg1, encoded by the NRG1 gene) improved cognitive deficits and reduced neuropathology in an Alzheimer's disease (AD) mouse model.

The growth factor neuregulin-1 is a key signaling factor controlling myelination in the peripheral nervous system via signaling through ErbB tyrosine kinase receptors. The neuregulins are a family of four structurally related proteins that are part of the EGF (epidermal growth factor) family of proteins, which have been shown to have diverse functions in the development of the nervous system.

Previous studies had suggested that Nrg1 signaling may influence cognitive function and neuropathology in AD. To test this possibility, investigators at the Salk Institute for Biological Studies (La Jolla, CA, USA) used a lentiviral vector to overexpress full-length type I or type III Nrg1 in the hippocampus of line 41 AD mice.

They reported in the August 25, 2016, online edition of the journal Scientific Reports that both type I and type III Nrg1 improved deficits in the Morris water-maze behavioral task, and significantly reduced neuropathology in the brains of the mice. The treated mice also displayed decreased expression of the neuronal marker MAP2 (Microtubule-associated protein 2) and synaptic markers PSD95 (postsynaptic density protein 95) and synaptophysin. Levels of A-beta peptides and plaques were markedly reduced.

In a series of follow-up experiments, the investigators showed that soluble ectodomains of both type I and type III NRG1 significantly increased the expression of the A-beta-degrading enzyme neprilysin (NEP) in primary neuronal cultures.

Results of this study suggested that Nrg1 provided beneficial effects in the mouse model of Alzheimer's disease and was a potential target for the treatment of AD.

"Neuregulin-1 has broad therapeutic potential, but mechanistically, we are still learning about how it works," said senior author Dr. Kuo-Fen Lee, professor of molecular neurobiology at the Salk Institute for Biological Studies. "We have shown that it promotes metabolism of the brain plaques that are characteristic of Alzheimer's disease."

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Salk Institute for Biological Studies