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New Study Directly Links Beta-CTF Protein to Pathology of Alzheimer’s Disease Development; Protein Acts at Earliest Stage of the Disease

A recent study conducted at the Nathan S. Kline Institute for Psychiatric Research (NKI) and the NYU Langone Medical Center implicates a new culprit in Alzheimer's disease (AD) development. The research reveals that C-terminal fragment beta (beta-CTF) -- the precursor of the amyloid beta (Aß) peptide -- acts at the earliest stage of Alzheimer's to initiate a range of abnormalities leading to the loss of groups of neurons critical for memory formation. Results from the study were published online on July 21, 2015 in the journal, Molecular Psychiatry, and the article has been selected for an issue cover. The article is titled “De Novo Deleterious Genetic Variations Target a Biological Network Centered on Aβ Peptide in Early-Onset Alzheimer Disease.” The recent study findings involving beta-CTF have significant implications for treatment strategies and furthering the course of Alzheimer's drug development. Presently, the most common strategy for treating AD is targeting the amyloid beta peptide, which has had modest success in clinical trials. Findings from this new research suggest that drugs that may reduce beta-CTF levels as well as beta-amyloid, such as the class of BACE1 inhibitors currently under development, may help slow or stop the progression of AD. Beta-CTF is formed during endocytosis, the process by which cells absorb nutrients and sample various materials from the outside environment. It has been known for some time that abnormalities of endocytosis develop very early in AD, well before clinical symptoms, and that variant forms of genes controlling endocytosis are frequently implicated as risk factors promoting Alzheimer's. Endosomes -- the membranous vesicles mediating endocytosis -- start to swell abnormally in some neurons beginning even in infancy in Down syndrome - a developmental disability that almost invariably leads to early-onset AD. Research indicates that more than 75 percent of those with Down's syndrome, aged 65 and older, have AD.

The NYU Langone/NKI research team, led by Ralph Nixon, M.D., Ph.D., Professor in the Departments of Psychiatry and Cell Biology at NYU Langone School of Medicine and Director of the Center for Dementia Research at the Nathan S. Kline Institute for Psychiatric Research found that, in Alzheimer's and Down syndrome, beta-CTF forms more rapidly on endosomes triggering a molecular pathway leading to loss of neurons involved with memory.

The researchers discovered that APPL1, a protein unrelated to amyloid precursor protein (APP) despite its similar abbreviation, directly links beta-CTF to a second protein, rab5, which is known to activate the molecular chain of events leading to neurodegeneration. Lowering APPL1 levels in cells of individuals with Down syndrome abolished the abnormal endocytosis, indicating the vital role of APPL1 in this molecular cascade.

The identification of APPL1 as the missing link in a well-described chain of events associated with very early Alzheimer pathology implies a direct contribution of beta-CTF to Alzheimer's disease development. Notably, a recently discovered APP mutation that uniquely lowers, rather than raising, risk for Alzheimer's is believed to act by slowing the formation of beta-CTF.

While the current findings do not place any more or less importance on Aß as a culprit and a target for Alzheimer's therapy, they now underscore the importance of beta-CTF as a key contributor to disease development.

"It will be important to consider the role of beta-CTF in the design of future therapies for Alzheimer's disease and in the interpretation of current clinical trials of BACE1 inhibitors. BACE1 inhibitor trials have been considered a test of the Aß/amyloid hypothesis but the primary action of these inhibitors is actually to block formation of beta-CTF, the precursor of Aß," said Dr. Nixon.

[Press release] [Molecular Psychiatry abstract]