Increased FMLN2 Expression and Reduced Clearance of Amyloid from the Aging Brain
Molecular waste, such as amyloid-β aggregates, is cleared from the brain via cerebrospinal fluid drainage and other paths such as direct entry into the circulatory system via the blood-brain barrier. A number of recent ventures have focused on the former path, such as Leucadia and EnClear, but here researchers suggest that biochemical changes in later life reduce passage of amyloid-β through the blood-brain barrier from the brain into the circulation. They implicate raised expression of one gene, FMNL2, but it remains to be seen as to (a) why this happens, how raised expression connects to the underlying damage of aging, and (b) how much of the pathology leading into neurodegeneration is mediated by FMLN2 and this pathway for removal of molecular waste from the brain.
A new study found a gene called FMNL2 links cerebrovascular disease and Alzheimer's and suggests changes in FMNL2 activity caused by cerebrovascular disease prevent the efficient clearance of toxic proteins from the brain, eventually leading to Alzheimer's disease. Researchers found FMNL2 in a genome-wide hunt designed to uncover genes associated with both vascular risk factors and Alzheimer's disease. The search involved five groups of patients representing different ethnic groups.
The blood-brain barrier is a semi-permeable, highly controlled border between capillaries and brain tissue that serves as a defense against disease-causing pathogens and toxins in the blood. Astrocytes, a specialized type of brain cell, compose and maintain the structure of the blood-brain barrier by forming a protective sheath around the blood vessel. This astrocyte sheath needs to loosen for the clearance of toxic amyloid - the aggregates of proteins that accumulate in the brain and lead to Alzheimer's disease.
A zebrafish model confirmed the presence of FMNL2 in the astrocyte sheath, which retracted its grip on the blood vessel once toxic proteins were injected into the brain, presumably to allow for clearance. When researchers blocked the function of FMNL2, this retraction did not occur, preventing clearance of amyloid from the brain. The same process was then confirmed using transgenic mice with Alzheimer's disease.
The same process may also occur in the human brain. The researchers studied postmortem human brains and found increased expression of FMNL2 in people with Alzheimer's disease, along with breach of the blood-brain barrier and retraction of the astrocytes. Based on these findings, the researchers propose that FMNL2 opens the blood-brain-barrier - by controlling its astrocytes - and promotes the clearance of extracellular aggregates from the brain. And that cerebrovascular disease, by interacting with FMNL2, reduces the clearance of amyloid in the brain.
Link: https://www.cuimc.columbia.edu/news/missing-link-between-alzheimers-and-vascular-disease-found