Project Details
Description
PROJECT SUMMARY
Type-2 diabetes mellitus (T2DM) sequelae damage the cerebral microvasculature and augment Alzheimer's
pathology by inducing brain insulin resistance characterized by sub-physiological insulin levels and impaired
insulin-signaling in the brain. Conversely, soluble amyloid beta (sAβ) peptides that accumulate in the plasma
and brain during Alzheimer's progression exacerbate the impact of T2DM and aggravate brain insulin
resistance. A critical need exists to identify how T2DM sequelae and sAβ exposure inhibit insulin delivery to
the brain and intensify brain insulin resistance. The long-term goal is to elucidate cerebrovascular and
metabolic contributions to Alzheimer's disease and facilitate the development of novel therapeutic
interventions. The overall objective in this application is to determine the combined effects of T2DM sequelae
and sAβ on insulin delivery to the brain and to identify the underlying cellular and molecular mechanisms. The
central hypothesis is that T2DM sequelae and sAβ peptides perturb insulin signaling/trafficking at the
cerebrovascular endothelium [referred to as the blood brain barrier (BBB)] and reduce insulin delivery to the
brain. It is also hypothesized that these effects are further aggravated by the pathological synergism between
T2DM sequelae and sAβ. The rationale for the proposed research is that a mechanistic understanding of how
sAβ exposure and T2DM sequelae disrupt brain insulin delivery will allow us to develop novel therapeutic
strategies to address brain insulin resistance in Alzheimer's disease and T2DM. Guided by preliminary data,
the following three specific aims are proposed: 1) Determine the effect of T2DM sequelae on insulin
trafficking/signaling at the BBB; 2) Determine the effects of sAβ alone and in conjunction with T2DM sequelae
on insulin trafficking/signaling at the BBB; and 3) Identify insulin trafficking pathways at the BBB, vulnerable
to sAβ exposure and impaired insulin signaling. Under the first and second aims, dynamic SPECT/CT imaging
will be used to characterize insulin uptake kinetics at the BBB in mouse models that exhibit T2DM and
Alzheimer's sequelae. Moreover, the dysregulation in insulin signaling at the BBB will be captured by reverse
phase protein arrays. For the third aim, flow cytometry and TIRF microscopy will be used to determine the
effects of sAβ ± insulin signaling inhibitors on insulin transcytosis in BBB monolayers. The proposed research
is potentially innovative because it employs dynamic imaging methods coupled with quantitative modeling
techniques to capture changes in insulin trafficking kinetics at the BBB in T2DM and Alzheimer's mouse
models. The proposed research is significant because the contribution it is expected to have broad translational
importance in repurposing existing drugs to treat brain insulin resistance and in identifying candidate targets
to discover novel drugs. Upon completion of the work, the new knowledge generated is expected to have an
important positive impact by facilitating the identification of novel therapeutic strategies to combat brain
insulin resistance in Alzheimer's patients with T2DM.
Status | Active |
---|---|
Effective start/end date | 3/1/22 → 2/28/25 |
Funding
- National Institute of Neurological Disorders and Stroke: $549,723.00
- National Institute of Neurological Disorders and Stroke: $529,773.00
- National Institute of Neurological Disorders and Stroke: $476,795.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.