Alzheimer’s Disease (AD) is a common form of dementia that may acquire epidemic proportions as the world population continues to grow progressively older. AD progressively disrupts memory and other cognitive abilities, and in its advanced stages impairs the individual’s ability to carry out even the most basic tasks of daily life. The pathogenic mechanisms of AD (deposition of amyloid plaques and tangles of altered tau protein) are still incompletely understood, and unfortunately effective disease modifying treatments are not yet available.
A recent study by Lu et al. (1) from Harvard identified REST, a neuro-protective nuclear protein which is lost in AD, but induced by Wnt signaling in normal aging brain to repress genes associated with cell death and AD pathology. 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. The authors found that in AD, frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB), REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins and that REST levels during ageing are closely correlated with cognitive preservation and longevity.
1- REST and stress resistance in ageing and Alzheimer’s disease. Lu T et al. Nature 2014;507:448-54. doi: 10.1038/nature13163. Epub 2014 Mar 19.
The findings are of considerable interest from a clinician’s perspective. There is not only a positive correlation between REST and various aspects of cognitive skill, but also an inverse relationship with the AD pathological load. This may help to explain why plaque and tangle pathology can be found in the brains of people who died without evidence of cognitive impairment. A second finding of clinical interest is the fact that the association between nuclear REST depletion and cognitive decline is not specific to AD. FTD and DLB are less common but equally devastating neurodegenerative conditions, with distinctive clinical patterns and neuropathology; REST depletion may be therefore be involved in a shared pathway to neurodegeneration.
Understanding why REST depletion occurs in some individuals and not others raises the possibility of disease prevention and treatment strategies. The molecular change may be associated with common and modifiable risk factors for dementia: raised plasma homocysteine, for instance, contributes up to 16% of the risk of late life dementia (2), yet the mechanism by which it does so is poorly understood. Similarly, a molecule that slows or stops REST from leaving the nucleus would be a novel and plausible approach to disease modification in established disease.
In summary, these new findings could lead rapidly to important advances in the understanding of the biology of neurodegenerative diseases, and to the development of rational therapeutic and preventative strategies for AD and other neurodegenerative diseases.
References 2- Plasma Homocysteine as a risk factor for dementia and |lzheimer’s Disease. Seshadri S et al. New England Journal of Medicine 2002;346:476-483.