PROJECT SUMMARY/ABSTRACT
Rare forms of familial Alzheimer disease (fAD) are known to be caused by life-long, genetically determined
perturbations in the production of the amyloid ß-protein (Aß), but the cause(s) of the vast majority of so-called
sporadic AD (sAD) cases remains remarkably poorly defined. This proposal will use state-of-the-art mouse
models of sAD together with several highly innovative approaches to address key temporal and spatial aspects
of sAD pathogenesis for the first time, with critical implications for the development of effective therapies.
Whereas fAD is attributable to chronic perturbations in the production of Aß, we hypothesize that sAD is triggered
by impairments in the clearance of Aß—specifically by transient impairments in Aß clearance. This hypothesis
is consistent with evidence showing that several established risk factors for sAD, such as brain trauma, stress,
or poor sleep, lead to short-lived or episodic increases in cerebral Aß levels due to reduced Aß clearance. To
model this novel mechanistic hypothesis, we employ innovative methods to inhibit Aß clearance transiently and
reversibly by blocking either blood-brain barrier transport of Aß or its proteolytic degradation. Because we aim
to define the triggers for sAD, we require an animal model that does not develop AD-type pathology on its own,
as most AD mouse models do. To this end, we will use an innovative new sAD mouse model, the APPNL-F/hAß
mice, which expresses wild-type human Aß only, under the control of the endogenous murine App promoter,
with the minimal genetic mutations needed to model sAD. As is true for normal humans, this sAD mouse model
develops diffuse deposits of human Aß in an age-dependent manner, and forms very minimal dense-core
plaques only at very advanced ages. Accordingly, these mice are ideal for investigating the pathophysiological
mechanisms responsible for triggering the conversion of “normal” Aß deposition to the pathological type in sAD.
We hypothesize further that the Aß-dependent pathological mechanisms most relevant to sAD occur much
earlier than the ages studied in clinical trials, with clinical symptoms emerging only much later, specifically in the
context of aging. Accordingly, we will define the temporal window most relevant to the emergence of AD by
increasing Aß levels in APPNL-F/hAß mice transiently at various ages, then evaluating the consequences for the
development of AD-type pathology longitudinally, up to and including old age.
Finally, we will test the novel hypothesize that spatially distinct pools of Aß (e.g., extra- vs. intracellular) impact
the pathogenesis of AD in qualitatively different ways. Specifically, we postulate that intracellular Aß is more
relevant than extracellular Aß to the neurodegeneration and memory loss that characterize AD. To test this, we
will selectively increase extra- vs. intracellular pools of Aß by reversibly downregulating Aß-degrading proteases
that, as our preliminary results show, selectively regulate these distinct pools of Aß. Collectively, these
experiments will allow us to investigate, cleanly and for the first time, many critical temporal and spatial aspects
of AD pathogenesis, yielding novel insights that will inform improved approaches to the treatment of sAD.