Increased Levels of Neuregulin-1 Reduce Amyloid Plaques and Improve Memory in a Mouse Model of Alzheimer's Disease

Researchers have recently demonstrated that raised levels of neuroregulin-1 in parts of the brain can reduce the build up of amyloid plaque and improve measures of memory in a mouse lineage engineered to reproduce the features of Alzheimer's disease. This is one of a range of methods that have shown improvements of one kind or another in a mouse model of Alzheimer's disease, and so far most have not exhibited useful results in human studies, or otherwise failed to make it much further along the path to the clinic. The degree to which particular models steer research in a useful direction is a legitimate question: Alzheimer's research is a field in which a great deal of debate, theorizing, and second guessing takes place precisely because meaningful results have yet to emerge from many years of large-scale investment. Given the history it is entirely appropriate to take a wait and see approach to this sort of thing. The reason I point out this research rather than any other is because it involves neuregulin-1.

If you wander the literature, or even just look back in the Fight Aging! archives, you'll find neuregulin-1 showing up in all sorts of interesting lines of research. Levels of neuregulin-1 are high in long-lived naked mole-rats and appear to vary by longevity in various rodent species. Increased neuregulin-1 in the heart has been shown to spur usually active regeneration, and bear in mind that the heart is an organ that normally regenerates poorly following damage in mammalian species. There are clinical trials at various stages for the use of neuregulin in heart failure patients. Higher levels of neuregulin-1 appear to slow kidney damage and might help with nerve repair as well. There are also lines of research that connect neuregulin-1 with exercise levels, making it yet another candidate for one of the myriad ways in which exercise produces health benefits, and others that link neuregulin-1 and related proteins with the exceptional regenerative capacity of species like salamanders and zebrafish. All in all this protein is something of a nexus for numerous distinct areas of research into regeneration and the effects of aging. That said, given all the other information, it is still perhaps a little surprising from an outside observer's perspective to find it reducing levels of amyloid - it doesn't quite follow the theme established above.

Elevating brain protein allays symptoms of Alzheimer's and improves memory

Boosting levels of a specific protein in the brain alleviates hallmark features of Alzheimer's disease in a mouse model of the disorder. The protein, called neuregulin-1, has many forms and functions across the brain and is already a potential target for brain disorders such as Parkinson's disease, amyotrophic lateral sclerosis and schizophrenia. Previously, researchers have shown that treating cells with neuregulin-1, for example, dampens levels of amyloid precursor protein, a molecule that generates amyloid beta, which aggregate and form plaques in the brains of Alzheimer's patients. Other studies suggest that neuregulin-1 could protect neurons from damage caused by blockage of blood flow.

In the new study, researchers tested this idea in a mouse model of Alzheimer's disease by raising the levels of one of two forms of neuregulin-1 in the hippocampus, an area of the brain responsible for learning and memory. Both forms of the protein seemed to improve performance on a test of spatial memory in the models. What's more, the levels of cellular markers of disease - including the levels of amyloid beta and plaques - were noticeably lower in mice with more neuregulin-1 compared to controls. The group's experiments suggest that neuregulin-1 breaks up plaques by raising levels of an enzyme called neprilysin, shown to degrade amyloid-beta. But that is probably not the only route through which neuregulin-1 confers its benefits, and the group is exploring other possible mechanisms - such as whether the protein improves signaling between neurons, which is impaired in Alzheimer's.

A neuregulin-1 treatment is not available on the market, though it is being explored in clinical trials as a potential treatment for chronic heart failure and Parkinson's disease. One advantage of neuregulin-1 as a potential drug is that it can cross the blood brain barrier, which means that it could be administered relatively noninvasively even though the efficiency is not clear. On the other hand, other research suggests too much of the protein impairs brain function. The team has come up with a small molecule that can raise levels of existing neuregulin-1 (rather than administering it directly) and are testing it in cells. This alternative therapy could be a better way to prevent plaques from forming because small molecules more readily cross the blood brain barrier.

Neuregulin 1 improves cognitive deficits and neuropathology in an Alzheimer's disease model

Several lines of evidence suggest that neuregulin 1 (NRG1) signaling may influence cognitive function and neuropathology in Alzheimer's disease (AD). To test this possibility, full-length type I or type III NRG1 was overexpressed via lentiviral vectors in the hippocampus of line 41 AD mouse. Both type I and type III NRG1 improves deficits in the Morris water-maze behavioral task. Neuropathology was also significantly ameliorated. Decreased expression of the neuronal marker MAP2 and synaptic markers PSD95 and synaptophysin in AD mice was significantly reversed. Levels of Aβ peptides and plaques were markedly reduced. Furthermore, we showed that soluble ectodomains of both type I and type III NRG1 significantly increased expression of Aβ-degrading enzyme neprilysin (NEP) in primary neuronal cultures. Consistent with this finding, immunoreactivity of NEP was increased in the hippocampus of AD mice. These results suggest that NRG1 provides beneficial effects in candidate neuropathologic substrates of AD and, therefore, is a potential target for the treatment of AD.


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