Will gene therapy help with Alzheimer's disease?
Specialists of the St. Jude Children's Research Clinic (Memphis, Tennessee), working under the guidance of Dr. Alessandra d'azzo, have found that the enzyme sialidase (neuraminidase-1, NEU1) is able to stop, and possibly even reverse the accumulation of plaques from the beta-amyloid protein, which are a kind of the "calling card" of Alzheimer's disease.
Neuraminidase-1 belongs to the class of enzymes responsible for the cleavage and processing of unnecessary proteins and other cellular debris occurring inside specialized structures – lysosomes.
The absence of this enzyme or a decrease in its activity level is characteristic of a rare hereditary disease – sialidosis, affecting children and adolescents. D'azzo's group has been studying this disease for a long time, as well as related conditions known as lysosomal accumulation diseases.
Previously, the authors demonstrated that neuraminidase-1 is necessary for the normal course of the process known as lysosomal exocytosis. Cells use this mechanism to repair damage to the outer membrane and selectively isolate waste material inside the lysosomes. Experiments on neuron cultures have shown that the absence of neuraminidase-1 is accompanied by an increase in the level of LAMP1 protein, which is a key regulator of lysosomal exocytosis. An increase in LAMP1 levels overly stimulates this process, which leads to an increase in the release of peptides associated with Alzheimer's disease by neurons.
Researchers have suggested that disorders in the functioning of neuraminidase-1 may be involved in the development of Alzheimer's disease. To test this hypothesis, they created a mouse model that does not have a functional NEU1 gene. In such animals, the loss of neuraminidase-1 activity led to the accumulation of amyloid precursor protein in lysosomes, which the authors identified as the direct target of the enzyme under study. If processed incorrectly, this protein is broken down into toxic peptides that form amyloid plaques. Based on the available scientific data, experts suggest that one of these peptides – beta-amyloid peptide-42 (Abeta-42) – plays a major role in the pathogenesis of Alzheimer's disease.
The study of brain tissue of mice without functional neuraminidase-1 showed not only that beta-amyloid fragments accumulate in lysosomes, but also that this process contributes to the production of Abeta-42 and other toxic peptides associated with Alzheimer's disease. Abeta-42 was identified in the cerebrospinal fluid and in the hippocampus of mice without the functional NEU1 gene, and was not detected in animals of the control group. The hippocampus, a region of the brain that plays a key role in learning and memorization, often suffers from the very early stages of Alzheimer's disease.
However, within a few weeks after the application of the gene therapy method developed by the authors, the purpose of which is to restore the activity of neuraminidase-1, a significant decrease in the number of amyloid plaques was observed in the hippocampus of experimental mice. This effect was achieved thanks to the viral vector modified by the authors, which delivers two therapeutic genes, NEU1 and PPCA, to animal brain cells at once. The protein encoded by the PPCA gene is necessary for the full functioning of neuraminidase-1.
According to the authors, the results obtained indicate not only that the lack of neuraminidase-1 is a risk factor for the development of Alzheimer's disease, but also the possibility of using this enzyme to slow down the progress of the disease, and possibly to eliminate the damage caused by it.
Article by Ida Annunziata et al. Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-beta secretion via deregulated lysosomal exocytosis is published in the journal Nature Communications.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of St. Jude Children's Research Hospital:
Gene therapy bolsters enzyme activity to combat Alzheimer’s disease in mice.
09.12.2013