An early precursor of the amyloid beta (Aß) peptide – ßCTF – has recently been implicated in the early development of Alzheimer’s disease. A study carried out by investigators at the Nathan S. Kline Institute for Psychiatric Research and New York University Langone Medical Center (both NY, USA) has demonstrated the role of ßCTF in the earliest stages of the disease, where it is responsible for the initiation of a number of abnormalities that lead to the loss of neurons critical for memory formation. The findings appeared recently in Molecular Psychiatry.
ßCTF is a protein formed during endocytosis – a process that is known to be dysfunctional in the very early stages of Alzheimer’s, prior to the manifestation of any symptoms. In this study, the team were able to demonstrate that in both Alzheimer’s disease and Down’s syndrome, βCTF developed more rapidly on endosomes. This swift development of ßCTF acts as a catalyst for a molecular pathway that results in the loss of neurons related to memory.
The team also uncovered the link between ßCTF and another protein termed APPL1. This effector protein was found to mediate interaction between ßCTF and the rab5 protein, which together are responsible for the activation of the molecular chain of events that lead to neurodegeneration. By lowering levels of APPL1 in cells of individuals with Down’s syndrome, the researchers were able to eliminate abnormal endocytosis – a finding that both implicates APPL1 as a ‘missing link’ in early Alzheimer’s disease processes and implies a direct contribution of ßCTF to Alzheimer’s disease development.
These findings could potentially have significant implications for the development of future Alzheimer’s therapies, suggesting that agents that may reduce levels of ßCTF as well as Aß may work to further slow disease progression, compared with current agents targeting Aß alone.
“It will be important to consider the role of βCTF 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 ßCTF, the precursor of Aß,” commented lead investigator Ralph Nixon (Langone School of Medicine).