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Study supports link between endosomal-traffic defect and Alzheimer’s

Science Translational Medicine
Reuters Health - 04/12/2020 - New findings confirm that endosomal-trafficking disruption is often involved in Alzheimer's disease.

Endosomes are part of the intracellular transport pathway to and from the cell membrane. Endosomal trafficking has recently been validated as a contributor to the pathogenesis of Alzheimer's disease, Dr. Scott A. Small of Columbia University Irving Medical Center, in New York City, explained in an email to Reuters Health.

"Still," he added, "it remained possible that this pathway causes the disease only rarely."

To investigate, Dr. Small and colleagues screened mice with a neuronal-selective knockout of the core of the retromer complex VPS35. This master conductor of endosomal traffic has been implicated in Alzheimer's disease.

The researchers validated "three of the most relevant proteomic findings," namely, the amino terminus of the transmembrane proteins APLP1 and CHL1, and the mid-domain of tau. They then set out "to determine the relationship of the three validated hits in the CSF of patients with AD with mild to moderate dementia."

Using an assay that they had developed, they found that in more than 300 such patients the concentration of amino-terminal APLP1 and CHL1 in the cerebrospinal fluid (CSF) correlated with tau and phosphorylated tau. Similar results were seen in healthy controls, where the proteins correlated with tau and phosphorylated tau and were elevated in about 70% of patients in the prodromal stages of AD.

Nevertheless, without a much larger number of prodromal patients and controls, say the researchers, "we cannot establish precise diagnostic cutoffs for n-APLP1 or n-CHL1, as they currently exist for tau."

"Based on the results," concluded Dr. Small, "this pathway is found in the majority of patients tested. This biomarker might also be used for future drugs that are being designed to correct the defective pathway."

The study had no commercial funding. Dr. Small and his coauthors are coinventors on patents related to the research.

SOURCE: https://bit.ly/2VB0r73 Science Translational Medicine, online November 25, 2020.

By David Douglas


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