Alzheimer's Disease-Related Dementias (ADRD) is a group of progressive neurodegenerative disorders with mid to late life onset such as mixed etiology dementias (MED) including Alzheimer's disease (AD) with TDP-43 pathology. To clarify disease mechanisms and identify therapeutic targets, a new mouse models that replicate combinations of co-occurring pathological features of human dementia will be critical. It is well recognized that AD cases with TDP-43 pathology, as compared to those without, showed a greater decline in cognitive deficits. However, the molecular mechanisms underlying such contribution of TDP-43 remains elusive. We showed that TDP-43 pathology is due to loss of TDP-43's nuclear function, particularly its ability to repress cryptic exon splicing, that precedes formation of TDP-43 cytoplasmic aggregates. That splicing repression is a major role of TDP-43 in forebrain neurons led us to hypothesize that loss of TDP-43 repression exacerbates neurodegeneration and cognitive deficits. To address this question, we will take advantage of 1) our model lacking TDP- 43 in forebrain neurons which exhibits age-dependent neuron loss, cognitive deficits and defects in prelimbic cortical circuits; and 2) our tau model which show, in presence of amyloid plaques, tauopathy- dependent neuron loss, to develop a novel MED model that would exhibit beta-amyloidosis and tauopathy along with compromised TDP-43 repression in forebrain neurons, pathological features that mimic AD with loss of TDP-43 repression. By employing a comprehensive set of molecular, pathological, neuronal circuit and behavioural/cognitive approaches, we will rigorously characterize the MED mice across their lifespan, providing a highly innovative and instructive model to clarify disease mechanism and identify therapeutic targets.

Public Health Relevance

Alzheimer's disease (AD) with TDP-43 pathology, one of the most common type of mixed etiology dementia (MED) that exhibit amyloid plaque, tauopathy and TDP-43 pathology, showed a greater decline in cognition and brain atrophy as compared to AD without TDP-43 pathology. However, the underlying pathogenic mechanisms remain elusive. In contrast to TDP-43 cytoplasmic aggregates, recent studies in human disease suggest that loss of TDP-43's nuclear function, particularly its ability to repress cryptic exon splicing, may contributes to such exacerbated outcomes, thus providing a strong scientific premise to develop a late life associated mouse model of MED for mechanistic and target identification studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Project #
1R61NS115161-01
Application #
9893402
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gubitz, Amelie
Project Start
2019-09-17
Project End
2022-08-31
Budget Start
2019-09-17
Budget End
2022-08-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pathology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205