title: Stimulating the Activity of Amyloid-Beta Degrading Enzymes: A Novel Approach for the Therapeutic Manipulation of Amyloid-Beta Levels.
abstract: Alzheimer's disease is a debilitating neurological disease placing significant burden on health care budgets around the world. It is widely believed that accumulation of amyloid-beta (Aβ) in the brain is a key event that initiates neurodegeneration, thus the clearance of Aβ from brain could be a key therapeutic strategy. Aβ exists in an equilibrium in healthy individuals, and recent research would suggest that dysfunction in the clearance pathways is the driving force behind its accumulation. One mechanism of clearance is proteolytic degradation by enzymes, and increasing the expression of these enzymes in animal models of Alzheimer's disease has indeed shown promising results. This approach could be challenging to translate into the clinic given the likely need for genetic manipulation. We hypothesize that stimulating the activity of these enzymes (as opposed to increasing expression) through pharmacological agents will enhance degradation or at least prevent amyloid deposition, and is therefore another potentially novel avenue to manipulate Aβ levels for therapeutic purposes. We discuss the recent research supporting this hypothesis as well as possible drawbacks to this approach.
authors: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC3800, Australia.
authors: Sanjaya
authors: S
authors: Kuruppu
authors: Baker IDI Heart and Diabetes Institute, Melbourne, VIC3004, Australia.|Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC3800, Australia.
authors: Niwanthi W
authors: NW
authors: Rajapakse
authors: Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC3800, Australia.
authors: Alexander J
authors: AJ
authors: Spicer
authors: Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC3800, Australia.
authors: Helena C
authors: HC
authors: Parkington
authors: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC3800, Australia.
authors: A Ian
authors: AI
authors: Smith
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020536:Enzyme Activators / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D015260:Neprilysin / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D020536:Enzyme Activators; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin
keywords: Alzheimer’s disease; amyloid-beta; enzymes; peptides