Enzyme that could lead to better diagnosis and treatment of Alzheimer’s disease identified

Washington – Researchers have identified an enzyme that could halt or possibly even reverse the build-up of toxic protein fragments known as plaques in the brains of mice with Alzheimer’s disease.

Plaques decreased substantially in mice treated with gene therapy to increase activity of the enzyme neuraminidase 1 (NEU1) in a region of the brain involved in learning and memory.

NEU1 belongs to a family of enzymes in cells whose job is to dismantle and recycle unneeded proteins and other components.

The enzyme is missing or reduced in a rare inherited disorder called sialidosis that can affect children and adolescents.

The work was done in a mouse lacking the NEU1 gene developed in laboratory of study’s corresponding author Alessandra d’Azzo, Ph.D., a member in the St. Jude Department of Genetics.

The study revealed that loss of NEU1 activity was linked with a build-up in lysosomes of the amyloid precursor protein (APP) that they identified as a natural target of the enzyme.

Improperly processed, APP is broken into the toxic peptides that form Alzheimer’s plaques. Those fragments include amyloid beta peptide 42 (A beta-42), which researchers suspect play a major role in the Alzheimer’s disease process.

Not only did APP accumulate in lysosomes of mice lacking NEU1 but researchers found evidence that the build-up promoted the production of A beta-42 and other toxic peptides tied to Alzheimer’s disease.
A beta-42 was detected in the spinal fluid and hippocampus of mice that lacked NEU1, but not in mice with a functional NEU1 gene.

Loss of NEU1 also accelerated the disease process in mice bred to mimic early-onset Alzheimer’s in humans. Without the enzyme, both APP and the protein fragments that make up plaques accumulated faster in these mice.

But within weeks of using gene therapy to bolster NEU1 activity, d’Azzo’s group reported that plaques declined dramatically in the hippocampus of treated mice.

The research has been published in the journal Nature Communications.