New study shows the brain’s ability to clear protein related to Alzheimer’s dementia is linked to the circadian rhythm.
Dementia or loss of memory is the seventh leading cause of death and one of the major causes of disability in older people worldwide. Alzheimer’s dementia (AD) is one such memory loss and neurodegenerative disorder which causes millions of deaths every year in the ageing population.
Alzheimer’s is a neuroinflammatory disease caused by impaired clearance of Amyloid ß42 (Aß42) protein, which forms plaques of alpha beta fibrils in the brain. Aß42 is the cleaved product of the amyloid precursor protein (APP). Aß42 is present in our cerebrospinal fluid and is important in neuronal growth and repair.
Despite studying AD for decades, the scientific and medical communities have not found a conclusive cure. This could be attributed to the complicated etiology of the disease. The possible risk factors that influence the progression of AD include dietary changes, nutrition, lifestyle habits, sleep patterns, environment, drug ingestion etc.
Scientists have discovered ways to reduce the severity of AD. Enhancing acetylcholine transmission, and drug delivery are some of the widely used treatments for AD. However, preventive and palliative care is extremely imperative in AD management.
Aß42 plaque formation heightens the immune response and causes inflammation in the body due to a surge of microglia and macrophages. This overactive immune function also results in cell death which in turn increases ROS (Reactive Oxygen Species) production in the brain and causes brain damage. This damage can be reduced to a certain extent by increasing antioxidant intake through diet. Scientists have conducted multiple clinical trials and after much debate, proved that Vitamin E or ɑ-Tocopherol can extend the lifespan of an AD patient by one year.
What impact does Circadian Rhythm have on Alzheimer’s?
Disrupted sleep-wake cycle and circadian rhythm are ever existing symptoms of AD. Initially, specialists considered disrupted circadian rhythms as a manifestation of the prevailing condition since AD patients do not have proper sleep patterns.
However, many experiments show that circadian loss happens much earlier in the disease progression and that some of the observed symptoms could be due to this disrupted cycle. Hence, sleep cycle and circadian rhythm disruption during the early stages or before the onset of the disease can prolong the devastating symptoms associated with AD.
Jennifer M. Hurley and her team at Rensselaer Polytechnic Institute, New York inspected the molecular connections between circadian rhythm and AD symptoms. They found that Aß42 is dependent on the circadian rhythm. Since the circadian rhythm is out of whack in AD patients, plaque development is not under check. They also showed that certain proteoglycans, (cell surface marker proteins) involved in clearing out these plaques are also under circadian control. Using cell culture of bone marrow cells from mice, they isolated the genes responsible for plaque clearance and checked their robust activity peak points using fluorescence imaging.
The researchers found that Aß42 proteins and proteoglycans are anti-phasic to each other i.e. their peak of activity is opposite to each other. Through various experiments, they indicated the functional relationship between the two proteins as proteoglycans rhythmically inhibit the phagocytosis of Aß42 proteins. These results of the study were published in PLOS Genetics.
Until this study, the role of circadian rhythm in AD was only explored in epidemiological and clinical studies. Prof. Hurley’s research uncovered the elusive biochemical interactions between them and further cemented the foothold for a better circadian rhythm to lessen the severe cognitive impairments. It also opens up gateways for drug targets and possibly, a cure for AD.
Research has time and time again stressed on the importance of circadian rhythm and sleep-wake cycle in cognitive and mental disorders. Industrialisation and lifestyle changes have made us neglect the benefits of a co-ordinated day-night cycle in our lives. It may not drastically affect everyone but it can cause mood disorders and in severe cases, early onset AD.
Aishwarya Segu is a PhD student from IISER Trivandrum who is fascinated with the working of the brain. She is a curious scientist, an avid reader and a trying writer.