Sumedha B S, Bangalore University
Alzheimer’s Disease- Cause Of Dementia In Older Adults
Alzheimer’s disease (AD) is a brain disorder that slowly destroys memory and thinking- a neurodegenerative disease. This damage initially takes place in the entorhinal cortex and hippocampus. It later affects areas in the cerebral cortex, which are responsible for language, reasoning, and behaviour. Most people have late-onset type symptoms which first appear in their mid-60s.
Alzheimer’s Disease is a neurodegenerative, neuroinflammatory disease. It is characterized by:
- extracellular β-amyloid (Aβ) plaques,
- intracellular hyperphosphorylated tau fibrils, and
- increased neuroinflammation
Amyloid-beta plaques:
Amyloid-beta (Aβ) is a product of proteolytic cleavage of a glycoprotein called Amyloid Precursor Protein (APP). The inability to clear amyloid-beta leads to its accumulation. APP plays an important role in neuronal development, signalling, intracellular transport, and neuronal homeostasis. Many APP cleavage products are known to be major contributors to Alzheimer’s disease.
AD has a two-way relationship with circadian disruption. Circadian disruption (CD) is a disturbance of biological timing, which can occur at different levels, ranging from molecular rhythms in individual cells to behavioural cycles. The molecular mechanism of the relationship between Circadian disruption and AD has not been elucidated yet. Although, myeloid phagocytosis is circadian-regulated. This offers a potential link between CD and AD.
Macrophages (microglia when in the brain), are immune cells that destroy unwanted material. These clear AB42 from the brain by ingesting it in a process called phagocytosis.
Understanding the metabolism of Aβ is essential to understanding Alzheimer’s disease and developing AD therapeutics.
How Circadian disruption is linked to Alzheimer’s Disease:
The immune cells responsible for the clearance of Aβ42 over the circadian period were studied at Rensselaer Center for Biotechnology and Interdisciplinary Studies.
A daily “oscillation” of Aβ42 levels in cerebrospinal fluid in healthy adults is observed. This oscillation is ablated in patients with AD. A physiological consequence of AD is the disruption of the circadian clock, the 24-hour endogenous rhythm that tunes physiology to the day/night cycle.
Clearance of Aβ is done by the microglial cells. It was found that in the later stages of AD the peripheral macrophages played a key role in Aβ Clearance. Neuroinflammation occurred due to the accumulation of Aβ42 plaques. This in turn elevated the levels of macrophage markers and activation of microglia. This increased peripheral macrophage migration across the blood-brain barrier.
Daily oscillation in Aβ42 clearance was recorded. It was observed that this oscillation was lost in cells without a circadian rhythm. They used bone-marrow-derived macrophages as a substitution for monocyte lineage cells to demonstrate that Aβ42 phagocytosis is under circadian control. Researchers found that the underlying cause of this oscillation was the circadian control of cell surface molecules- heparan sulfate proteoglycans (HSPGs). Transcriptomic and proteomic data were used to identify a few components that are circadian regulated in the phagocytosis pathways. Analysis of this data suggested that the presence of proteoglycans suppresses the phagocytosis of Aβ42. Also, the key factor in the circadian timing of Aβ42 phagocytosis was the presence of cell-surface HSPGs. This regulation was specific to Aβ42.
Thus, the study gives an insight into the mechanistic link between the disruption of circadian rhythms and AD. Research also concluded that the disruption of circadian rhythms can lead to enhanced AD pathogenesis.
Significance of the study:
As it was found that proteoglycans play critical roles in cellular processes, it is likely that PGs regulate the circadian clock in other tissue types too. This makes it a promising target for future circadian studies.
The study demonstrates the importance of healthy sleep habits in preventing Aβ42 plaques in the brain. This opens a path to potential Alzheimer’s therapies.
The circadian regulation of HSPG could be critical to preventing hyper-inflamed states in inflammatory diseases such as AD.
The removal of Aβ42 is vital for a healthy neuronal microenvironment. This study is the first to demonstrate a link between the circadian timing of HSPGs and Aβ42 clearance.
Also read: The neural description of nostalgic smells
Reference:
1) Clark GT, Yu Y, Urban CA, Fu G, Wang C, Zhang F, et al. (2022) Circadian control of heparan sulfate levels times phagocytosis of amyloid-beta aggregates. PLoS Genet 18(2): e1009994. https://doi.org/10.1371/journal.pgen.1009994
2) Rensselaer Polytechnic Institute. (2022, February 10). Clearance of protein linked to Alzheimer’s controlled by circadian cycle: Ability of immune system to destroy Alzheimer’s-related protein oscillates with daily circadian rhythm. ScienceDaily. Retrieved March 3, 2022 from www.sciencedaily.com/releases/2022/02/220210154215.htm
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