Affiliations: [a] Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC3800, Australia
| [b]
Baker IDI Heart and Diabetes Institute, Melbourne, VIC3004, Australia
| [c] Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC3800, Australia
| [d] Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC3800, Australia
Correspondence:
[*]
Correspondence to: Sanjaya Kuruppu, Department of Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Tel.: +61 3 9902 9372; Fax: +61 3 9905 5645; E-mail: [email protected].
Note: [1] Faculty of Health and Wellbeing, Sheffield Hallam University, Sheffield, South Yorkshire, UK.
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.
