Researchers identified a new precursor protein in the earliest stages of Alzheimer’s disease that begins the chain of processes leading to the loss of vital neurons in memory formation, according to a study published in the journal Molecular Psychiatry.
The researchers found βCTF, the precursor of the amyloid beta (Aβ) peptide that forms on endosomes that sets off a molecular pathway that leads to neurodegeneration in Alzheimer’s and Down Syndrome. βCTF is formed during endocytosis causing endosomes to swell in neurons. Abnormalities in endocytosis develop before any signs of clinical symptom and its variant genes are often associated as risk factors promoting Alzheimer’s.
The research team also identified APPL1 that links βCTF to a second protein, rab5, that all act to spur a cascade of events leading to neuron loss. Research findings show that lowering APPL1 levels in patients with Down Syndrome eliminated the abnormal endocytosis. APPL1 and βCTF both play critical roles in early Alzheimer pathology.
A class of drugs currently under development, BACE1 inhibitors, may help slow or stop the progression of Alzheimer’s by working to reduce both βCTF and β-amyloid levels. The research team head, Ralph Nixon, MD, PhD, concluded that current findings do not downsize the importance of Aβ as a target for Alzheimer’s therapy, but highlights the importance of considering the role of βCTF in the development of future screening and treatment strategies for Alzheimer’s disease.
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