April 18, 2014

Important new molecule in the biology of dementia

Anthony L. Komaroff, NEJM Journal Watch, April 8, 2014

Two molecules — β-amyloid and tau — are important in the biology of Alzheimer disease. Yet, high concentrations of them, either alone or together, do not seem to be sufficient to cause the disease.

In a study in the March 27 issue of Nature (http://dx.doi.org/10.1038/nature13163), researchers evaluated the molecules produced in the brains of older people with preserved cognitive function or with dementia and identified a candidate molecule called REST, which is important in embryonic brain development. The production of REST is silenced after embryonic development is completed, but is turned back on in aging brains. The researchers discovered that production continues in healthy older people with preserved cognition — but switches off in people with mild cognitive impairment, Alzheimer disease, or one of several other dementing diseases. REST deficiency was most striking in areas that are most affected in Alzheimer disease. Experiments showed that REST protects neurons from the toxic effects of β-amyloid and oxidative stress and protects against apoptosis (which is programmed cell death). Deleting the gene for REST in mice led to age-related neurodegeneration.

The REST molecule might protect the brain against age-related degenerative diseases, including Alzheimer disease. This molecule now becomes an important focus in understanding the underlying biology of dementia, as well as a target for therapeutics. Not all new and exciting putative disease-related molecules stand the test of time, but many experts are betting that this one will.

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REST and stress resistance in ageing and Alzheimer’s disease

Tao Lu, Liviu Aron, Joseph Zullo, Ying Pan, Haeyoung Kim, Yiwen Chen, Tun-Hsiang Yang, Hyun-Min Kim, Derek Drake, X. Shirley Liu, David A. Bennett, Monica P. Colaiácovo & Bruce A. Yankner

Nature 507, 448–454 (27 March 2014) doi:10.1038/nature13163


Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer’s disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer’s disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer’s disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.