Development of sAPPβ and sAPPα as Biomarkers of BACE1 Activity: Implications for Differentiation of Alzheimer's Disease Subgroups

Project: Research project

Project Details

Description

It is unclear why certain individuals accumulate Aβ while others do not. Aβ clearance slows with age, and we know Aβ42 kinetics are significantly altered with amyloidosis, but we still don’t know how much Aβ42 production plays a role in Aβ accumulation in sporadic AD. For example, Mattsson et al. recently showed that CSF Aβ38 and Aβ40, as surrogate markers of Aβ production, were elevated in humans with amyloid deposition. Moreover, the correlation between Aβ38 and Aβ40 and amyloid load was most pronounced in subjects negative for ApoE4. Since ApoE4 reduces Aβ clearance, the correlation between Aβ38 and Aβ40 and amyloid load in ApoE4 negative subjects indicates a subgroup of individuals in which the mechanism of Aβ accumulation is not simply due to decreased clearance. Rather, ApoE4 negative individuals may have increased Aβ production, similar to, but maybe not the same magnitude as, early-onset autosomal dominant AD. Additionally, Dr. Zakaria’s 2014 PLoS One paper showed a shift from α- to β-secretase processing of APP from 3:1 in controls to 2:1 in the setting of amyloid deposition in the brain. Finally, her current preliminary results (Fig. 2) show that newly generated sAPPβ, as well as the absolute ratio of newly generated sAPPβ:sAPPα, were significantly elevated in the CSF of amyloid-positive subjects. Taken as a whole, these studies strongly suggest the existence of a role of production, or the possibility of subgroups of individuals that accumulate Aβ because of increased Aβ generation that may result from elevated BACE1 processing of APP, at least in part, together with decreased Aβ clearance.
We anticipate that kinetic rates of sAPPβ and sAPPα as biomarkers of BACE1 activity, together with kinetic rates of Aβ isoforms, will allow determination of a pathophysiological mechanism of increased production that may precede or accompany amyloidosis. The current study may provide proof of concept for elevated BACE1 activity, although a longitudinal study (in a subsequent R01) will address factors and timing that drive the BACE1 increase. The hypothesis is that increased BACE1 activity would exhibit increased newly generated sAPPβ, Aβ38, Aβ40, and Aβ42, resulting in decreased newly generated sAPPα. Other alternative hypotheses of Aβ accumulation exist. For example, some individuals may have increased γ-secretase cleavage at amino acid 42 of the Aβ sequence, as opposed to 38 or 40, thus elevating the ratio of the absolute production rate of Aβ42/Aβ40 and Aβ42/Aβ38 without a change in sAPPβ or sAPPα. A third hypothesis is that some individuals have increased total APP expression, in which case all APP proteolytic products would be elevated. A fourth hypothesis is that some individuals may have reduced Aβ clearance, such that no change would be apparent in sAPPβ or sAPPα but rather Aβ42 aggregation rate would be increased. These mechanisms of pathogenesis are not mutually exclusive, e.g. an individual with decreased Aβ clearance may also have increased BACE1 activity. Demonstration of such pathophysiological mechanisms will inform about basic mechanisms of physiological and pathological processing of APP. Additionally, sAPPβ and sAPPα may serve as useful biomarkers for early presymptomatic AD.
StatusFinished
Effective start/end date10/1/176/1/20

Funding

  • F-Prime Inc. (FPI Agmt Signed 10/09/17)

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