Cure Alzheimer's Fund: Targeting Breakthrough Research

During the past year, our laboratory at UCSD (Wagner laboratory), in close collaboration with the Tanzi laboratory at MGH, discovered, synthesized and characterized (in vitro) a novel series of molecules able to potently prevent the formation of what is currently thought to be the pathogenic culprit of Alzheimer’s disease (AD).

The hypothesis of this proposal is that a method can be developed to measure tau levels in the extracellular space of the brain (interstitial fluid–ISF) and that assessment of ISF tau in both normal mice as well as a variety of animal models that develop AD pathology will provide new insights into tau metabolism and the relationship between Aβ and tau in AD. If this method development is successful, it has a chance to tell us more about the pathophysiology of AD as well as a provide a novel way to screen for new AD treatments.

Excessive synaptic loss is thought to be one of the earliest events in Alzheimer’s disease (AD). In our previous studies, we have shown that amyloid beta (Aβ), a peptide implicated in the pathogenesis of AD, is secreted in an activity-modulated manner. Furthermore, we found that secreted Aβ leads to loss of synaptic receptors (by endocytosis), synaptic depression and removal of dendritic spines, sites of excitatory synaptic transmission.

While the mechanism of Aβ cytotoxicity remains contentious, evidence is accumulating that membrane permiabilization plays a key role in the pathological activity of the peptide. This study will focus on role of Aβ oligomerization in the Aβ-mediated disruption of lipid bilayers.

The objective of this proposal is to determine the effect of physiological alterations in neuronal activity on ISF Aβ levels in vivo. Such information may provide important information as to how to potentially regulate the probability of whether or not Aβ will or will not ultimately aggregate in the brain and initiate the process we know of as AD. We will utilize in vivo microdialysis with concurrent electrophysiological recordings to determine how physiological changes in neuronal activity dynamically affects ISF Aβ.

The specific hypothesis behind the proposed research is that presenilin 1 regulates cell fate determination of adult neural progenitor cells by interfering with instructive intercellular signals prevailing within the neural progenitor cell niche, and that expression of the familial AD-linked presenilin 1adversely affects this process.

Investigating the increasingly documented link between TBI/stroke and Alzheimer’s disease is aimed not only at developing effective interruptions of that linkage but also a contribution to an understanding of the basic Alzheimer’s disease mechanism.

We have coined the term CAPS to describe cross-linked-Beta-amyloid protein species. CAPS, particularly dimeric forms, are highly neurotoxic. CAPS are also abundant in vivo, with dimeric species alone comprising as much as 40 percent of the total Abeta pool in late state AD brain. In this study we plan to screen compound libraries for potential therapeutic agents that attenuate the levels and/or cytotoxic activity of CAPS.