βA4 amyloid peptide, the main constituent of amyloid plaques and cerebrovascular amyloid deposits associated with Alzheimer's disease, derives from a large precursor protein (APP) by the action of β- and γ-secretases, the unidentified endoproteases which release the amino and carboxyl termini of βA4, respectively. Several γ-secretase cleavage sites exist which yield the more soluble (1-39/40) forms of βA4 and the longer forms (1-42/43) which have a greater tendency to aggregate into amyloid plaques. γ-Secretase activity may therefore be critical in amyloid formation. In this study, a synthetic peptide which encompasses the various γ-secretase cleavage sites was used as a substrate to probe proteases of various classes and specificities. Elastase, collagenase, and cathepsin D cleaved at the amyloidogenic sites (after Ala42 or after Thr43) to release the carboxyl termini of the aggregating forms. In addition, collagenase and pepsin released the carboxyl terminus of the more soluble forms. Human brain fractions enriched in lysosomes contained a proteolytic activity that cleaved the substrate at the amyloidogenic site(s). This activity was more active at acidic pH and was inhibited by pepstatin, two characteristics of the lysosomal aspartyl proteinase cathepsin D. The same lysosomal fractions were found to contain APP carboxyl-terminal fragments which are potentially amyloidogenic. These were degraded, only in acidic conditions, by an endogenous protease activity inhibited by pepstatin. Thus, a cathepsin D- like activity from human brain is a candidate for APP γ-secretase(s).

Item Type:	Refereed Article
Research Division:	Biomedical and Clinical Sciences
Research Group:	Neurosciences
Research Field:	Neurosciences not elsewhere classified
Objective Division:	Health
Objective Group:	Clinical health
Objective Field:	Clinical health not elsewhere classified
UTAS Author:	Small, DH (Professor David Small)
ID Code:	75426
Year Published:	1995
Web of Science® Times Cited:	80
Deposited By:	Research Division
Deposited On:	2012-01-30
Last Modified:	2013-05-07
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