New Culprit in Alzheimer’s Disease Development Identified

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A recent study conducted at Nathan S. Kline Institute for Psychiatric Research (NKI) and NYU Langone Medical Center implicates a new culprit in Alzheimer’s disease development. The research reveals that ßCTF — the precursor of the amyloid beta (Aß) peptide — acts at the earliest st

Findings may influence strategies for treatment.

A recent study conducted at Nathan S. Kline Institute for Psychiatric Research (NKI) and NYU Langone Medical Center implicates a new culprit in Alzheimers disease development. The research reveals that CTF the precursor of the amyloid beta (A) peptide acts at the earliest stage of Alzheimers to initiate a range of abnormalities leading to the loss of groups of neurons critical for memory formation. Results from the study are published online July 21, 2015 in the journal,Molecular Psychiatry, and the article has been selected for an issue cover.

The recent study findings involving CTF have significant implications for treatment strategies and furthering the course of Alzheimers drug development. Presently, the most common strategy for treating Alzheimers disease is targeting the amyloid peptide, which has had modest success in clinical trials. Findings from this research suggest that drugs that may reduce 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 Alzheimers disease.

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 Alzheimers disease, well before clinical symptoms, and that variant forms of genes controlling endocytosis are frequently implicated as risk factors promoting Alzheimers. 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 Downs, aged 65 and older, have Alzheimers disease.

Researchers found that, in Alzheimers and Down Syndrome, CTF forms more rapidly on endosomes triggering a molecular pathway leading to loss of neurons involved with memory. The researchers discovered APPL1, a protein unrelated to amyloid precursor protein (APP) despite its similar acronym, directly links CTF to a second protein, rab5, known to activate the molecular chain of events leading to neurodegeneration. Image is for illustrative purposes only.

The NYU Langone NKI research team led by Ralph Nixon, MD, PhD, 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 Alzheimers and Down Syndrome, CTF forms more rapidly on endosomes triggering a molecular pathway leading to loss of neurons involved with memory. The researchers discovered APPL1, a protein unrelated to amyloid precursor protein (APP) despite its similar acronym, directly links CTF to a second protein, rab5, 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 CTF to Alzheimers disease development. Notably, a recently discovered APP mutation that uniquely lowers, rather than raising, risk for Alzheimers is believed to act by slowing the formation of CTF.

While the current findings do not place any more or less importance to A as a culprit and a target for Alzheimers therapy, they now underscore the importance of CTF as a key contributor to disease development. It will be important to consider the role of CTF in the design of future therapies for Alzheimers disease and in the interpretation of current clinical trials of BACE1 inhibitors. BACE1 inhibitor trials have been considered a test of the A/amyloid hypothesis but the primary action of these inhibitors is actually to block formation of CTF, the precursor of A, said Ralph A. Nixon, MD, PhD.

Source:Camy Sleeman Nathan S. Kline Institute for Psychiatric Research