New Potential Therapeutic Target For Alzheimer’s Disease: Beta-CTF
Researchers at New York University Langone Medical Center and the Nathan S. Kline Institute for Psychiatric Research (NKI) in New York recently discovered a potential therapeutic target for Alzheimer’s disease and provided more insight into the associated endosome dysfunction. The study was published in the journal Molecular Psychiatry and is entitled “Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer’s disease”.
Alzheimer’s disease is a neurodegenerative disorder characterized by cognitive and behavioral problems. Patients initially experience memory loss and confusion that gradually leads to behavior and personality changes, a decline in cognitive abilities and ultimately to severe loss of mental function. Alzheimer’s disease is characterized by the formation of amyloid plaques in the brain [aggregates of beta-amyloid proteins derived from the beta-amyloid precursor protein (APP)], and the loss of neurons responsible for memory and learning. Alzheimer’s disease is estimated to affect more than 36 million individuals worldwide, and is the most common form of dementia in the elderly population. Currently there are no drugs available to either stop or stabilize disease progression.
Endosomes are membrane-bounded compartments inside cells that sort the destiny of molecules, including degradation and recycling. Endosomes are highly active APP processing sites, where APP is processed into its cleaved products. Endosomal abnormalities due to the upregulation of an early endosomal regulator called rab5, correspond to the earliest known disease-specific neuronal response in Alzheimer’s patients. Endosomes were shown to swell abnormally in some neurons, a phenomenon that can begin in infancy as reported in cases of Down syndrome, a genetic disorder also known as trisomy 21 characterized by characteristic facial features, delayed growth and intellectual disability. Down’s syndrome leads to early-onset Alzheimer’s disease. It is estimated that 75% of all Down syndrome patients who are aged 65 or older develop Alzheimer’s disease.
Researchers have now reported that in disorders like Alzheimer’s and Down syndrome a molecule called beta-CTF (beta-cleaved carboxy-terminal fragment of APP) forms more rapidly on endosomes inducing a pathway that ultimately leads to the loss of neurons crucial for memory formation.
Researchers discovered that beta-CTF is linked to rab5 through a third protein known as APPL1. The decrease in APPL1 levels in cells from Down syndrome patients was found to abolish the abnormal endocytic process. According to the team, high levels of beta-CTF trigger APPL1, which in turn mediates endosomal rab5 over-activation in Alzheimer’s and Down syndrome.
The research team concluded that APPL1 is the missing link between beta-CTF and endosomal abnormalities, and suggest that their findings underscore the importance of beta-CTF in Alzheimer’s disease development and its potential use as a therapeutic target.
“It will be important to consider the role of β[beta]CTF in the design of future therapies for Alzheimer’s disease and in the interpretation of current clinical trials of BACE1 inhibitors (…) the primary action of these inhibitors is actually to block formation of ßCTF,” concluded the study’s senior author Dr. Ralph A. Nixon in a news release.