Project 2 of the Johns Hopkins Alzheimer's Disease Research Center (ADRC) is titled """"""""Modeling an anti-amyloid therapy for AD: potential for cognitive recovery"""""""". This project focuses the role of oligomeric amyloid-beta (A-beta) peptides in the cognitive impairment associated with Alzheimer's disease (AD). The project will test the hypothesis that accumulation of oligomeric A-beta species impairs learning and memory and that these cognitive impairments can be reversed with suppression of A-beta generation. To address this question we will use a mouse model of A-beta amyloidosis in which the expression of mutant amyloid precursor protein (APP) is controlled by a tetracycline-regulated promoter (these transgenic mice are known as TetOffAPP mice). A-beta production can be suppressed in these mice with doxycycline. Preliminary data suggest that following A-beta suppression with doxycycline, amyloid deposits are stable but there is, nevertheless, a gradual amelioration of the memory deficits. This finding has led to the following three specific aims: (1) Aim 1: To determine whether the reduction of oligomoeric A-beta species derived from newly-synthesized A-beta peptides improves learning and memory in the conditional TetOffAPP mouse models after genetically induced arrest of APP expression and new A-beta production. (2) Aim 2: To determine whether recovery of synaptic damage is associated with cognitive improvement after A-beta production - synaptic, glutamatergic and immediate early gene markers of neuronal activity will be assessed in mice with significant amelioration of memory deficits. (3) Aim 3: To examine the role of neurodegenerative changes in CNS monoamine systems in relation to the degree of cognitive recovery observed after reduction of A-beta peptides in the TetOffAPP mice. Collectively, outcomes from these studies will address an important issue regarding the value of an anti-amyloid therapeutic strategy for AD by assessing the magnitude of functional repair and recovery after synaptic damage by oligomeric A-beta. Evaluation of outcomes of therapeutic interventions that target A-beta production will inform appropriate expectations in clinical trials.

Public Health Relevance

Understanding mechanisms that influence the pathology of Alzheimer's disease, and whether it is possible to reduce pathology once it has developed, is of crucial importance in developing strategies to combat Alzheimer's disease, a neurodegenerative disorder which affects over 6 million Americans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005146-29
Application #
8441072
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
29
Fiscal Year
2012
Total Cost
$220,775
Indirect Cost
$86,156
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Brent, Robert J (2018) Estimating the monetary benefits of medicare eligibility for reducing the symptoms of dementia. Appl Econ 50:6327-6340
van Bergen, Jiri M G; Li, Xu; Quevenco, Frances C et al. (2018) Low cortical iron and high entorhinal cortex volume promote cognitive functioning in the oldest-old. Neurobiol Aging 64:68-75
Kim, Sangjune; Yun, Seung Pil; Lee, Saebom et al. (2018) GBA1 deficiency negatively affects physiological ?-synuclein tetramers and related multimers. Proc Natl Acad Sci U S A 115:798-803
Deming, Yuetiva; Dumitrescu, Logan; Barnes, Lisa L et al. (2018) Sex-specific genetic predictors of Alzheimer's disease biomarkers. Acta Neuropathol 136:857-872
Burke, Shanna L; Maramaldi, Peter; Cadet, Tamara et al. (2018) Decreasing hazards of Alzheimer's disease with the use of antidepressants: mitigating the risk of depression and apolipoprotein E. Int J Geriatr Psychiatry 33:200-211
Hohman, Timothy J; Dumitrescu, Logan; Barnes, Lisa L et al. (2018) Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. JAMA Neurol 75:989-998
Kageyama, Yusuke; Saito, Atsushi; Pletnikova, Olga et al. (2018) Amyloid ? toxic conformer has dynamic localization in the human inferior parietal cortex in absence of amyloid plaques. Sci Rep 8:16895
Kales, Helen C; Gitlin, Laura N; Stanislawski, Barbara et al. (2018) Effect of the WeCareAdvisor™ on family caregiver outcomes in dementia: a pilot randomized controlled trial. BMC Geriatr 18:113
Qian, Winnie; Fischer, Corinne E; Schweizer, Tom A et al. (2018) Association Between Psychosis Phenotype and APOE Genotype on the Clinical Profiles of Alzheimer's Disease. Curr Alzheimer Res 15:187-194
Reagh, Zachariah M; Noche, Jessica A; Tustison, Nicholas J et al. (2018) Functional Imbalance of Anterolateral Entorhinal Cortex and Hippocampal Dentate/CA3 Underlies Age-Related Object Pattern Separation Deficits. Neuron 97:1187-1198.e4

Showing the most recent 10 out of 830 publications