Alzheimer's disease (AD) is a global health crisis. In US alone, ~5.4 million Americans are afflicted with AD, and this number may escalate up to ~16 million if effective treatments are not discovered. Emerging evidence indicates a causal link between type 2 diabetes (T2DM) and AD. Both T2DM and AD exhibit hyperglycemia, insulin resistance and insulin receptor(s) (IRS1/2) dysfunction. Insulin acts as a neuroprotective factor, supports neuronal repair, dendritic sprouting and differentiation which logically led to insulin therapy. However, Insulin is likely to produce hypoglycemia and elevate Ass due to its competition with insulin degrading enzyme (IDE) that degrades both insulin and Ass. Therefore, approaches that reduce hyperglycemia other than insulin are emerging. One such approach is the use of incretins-a group of gut hormones-such as Glucagon-like peptide 1 (GLP1), that stimulates insulin release during hyperglycemia, while simultaneously preventing hypoglycemia and maintaining euglycemia. GLP1 is neuroprotective acting via GLP1 receptors (GLP1R) expressed on neurons and is known to improve learning and memory. GLP1 is degraded by dipeptidyl- peptidase 4 (DPP-4) with a half life of 1-2 min in humans, which resulted in the development of DPP-4 resistant more stable and longer lasting GLP1 mimetics such as Exendin-4 (Ex-4) (Byetta) and Liraglutide (Victoza). However, long-term systemic use of these GLP1 analogues is reported to cause pancreatitis and renal failure. In order to circumvent these adversities, we propose intranasal route of delivery of GLP1 which is previously shown to be successful, but with the novel modification of conjugating GLP1 with wheat germ agglutinin (WGA)-a biologically-derived non-immune and non-toxic glycoprotein. WGA conjugation to GLP1 not only will enhance intranasal delivery of GLP1, but will also exert additive insulinotropic effects and thus will validate advanced incretin therapy for AD. We have already tested the feasibility of intranasal administration of WGA- labeled GLP1 (WGA-GLP1) to the brain in 5XFAD mice modeling AD, which strengthens successful achievement of proposed aims. This project will test the hypothesis that Intranasal delivery of WGA conjugated GLP1 (WGA-GLP1) will more efficiently prevent and reverse AD-like pathocognition than the unconjugated GLP1 (GLP1) in 5XFAD mice. If successful, this project has great potential for clinical translation.

Public Health Relevance

Effective disease-modifying therapies are needed to treat Alzheimer's disease (AD) currently afflicting ~5.4 million Americans with projected escalation of people with AD up to >16 million. Proposed intranasal administration of WGA conjugated GLP1 (WGA-GLP1), both for enhancing intranasal delivery of therapeutics to the brain and for extending insulinotropic effects while simultaneously circumventing systemic adversities, is the pre-clinical stepping stone towards the validation of advanced incretin therapy for AD. Proposed pre-clinical evaluation of therapeutic efficacy of intranasally delivered WGA-GLP1 will offer a safe, practical and novel therapy for AD with a great potential of clinical translation. NOTE: The critiques and criterion scores from individual reviewers are provided below in an essentially unedited form. These were prepared prior to the review meeting and may not have been updated or revised subsequent to the discussion at the meeting. Therefore, they may not fully reflect the final opinions of the individual reviewers at the close of group discussion or th final majority opinion of the group. The Resume and Summary of Discussion above summarizes the final outcome of the group discussion.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS079614-01A1
Application #
8512104
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Corriveau, Roderick A
Project Start
2013-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$239,250
Indirect Cost
$89,250
Name
University of Illinois at Chicago
Department
Pediatrics
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Chauhan, Neelima B (2014) Chronic neurodegenerative consequences of traumatic brain injury. Restor Neurol Neurosci 32:337-65
Mehla, Jogender; Chauhan, Balwantsinh C; Chauhan, Neelima B (2014) Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits. J Alzheimers Dis 39:145-62
Xiao, Chun; Davis, Francesca J; Chauhan, Balwantsinh C et al. (2013) Brain transit and ameliorative effects of intranasally delivered anti-amyloid-ýý oligomer antibody in 5XFAD mice. J Alzheimers Dis 35:777-88