Cathepsin B Improves ß-Amyloidosis and Learning and Memory in Models of Alzheimer's Disease.

Abstract

Amyloid-ß (Aß) precursor protein (APP) metabolism engages neuronal endolysosomal pathways for Aß processing and secretion. In Alzheimer's disease (AD), dysregulation of APP leads to excess Aß and neuronal dysfunction; suggesting that neuronal APP/Aß trafficking can be targeted for therapeutic gain. Cathepsin B (CatB) is a lysosomal cysteine protease that can lower Aß levels. However, whether CatB-modulation of Aß improves learning and memory function deficits in AD is not known. To this end, progenitor neurons were infected with recombinant adenovirus expressing CatB and recovered cell lysates subjected to proteomic analyses. The results demonstrated Lamp1 deregulation and linkages between CatB and the neuronal phagosome network. Hippocampal injections of adeno-associated virus expressing CatB reduced Aß levels, increased Lamp1 and improved learning and memory. The findings were associated with the emergence of c-fos + cells. The results support the idea that CatB can speed Aß metabolism through lysosomal pathways and as such reduce AD-associated memory deficits.

• Authors: Christine M Embury, Bhagyalaxmi Dyavarshetty, Yaman Lu, Jayme L Wiederin, Pawel Ciborowski, Howard E Gendelman, Tomomi Kiyota
• Journal: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology (J Neuroimmune Pharmacol) Vol. 12 Issue 2 Pg. 340-352 (06 2017) ISSN: 1557-1904 [Electronic] United States
• PMID: 27966067 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Protein Precursor
• Presenilin-1
• Cathepsin B

Topics

• Alzheimer Disease (drug therapy, metabolism, pathology)
• Amyloid beta-Protein Precursor (metabolism)
• Amyloidosis (drug therapy, pathology)
• Animals
• Cathepsin B (pharmacology, therapeutic use)
• Disease Models, Animal
• Hippocampus (drug effects, pathology)
• Learning (drug effects, physiology)
• Maze Learning (drug effects, physiology)
• Memory (drug effects, physiology)
• Memory Disorders (drug therapy, metabolism, pathology)
• Mice
• Mice, Transgenic
• Presenilin-1 (metabolism)