Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and impairments in other aspects of cognitive and behavioral function. It is the most common form of dementia, currently afflicting roughly five million Americans, a number projected to quadruple by 2050. Neuropathologically, AD is defined by the accumulation of extracellular plaques composed of beta-amyloid (A?), and intracellular neurofibrillary tangles (NFTs), consisting of phosphorylated forms of the microtubule- associated protein, tau. Mutations in three separate genes have been linked to the rare (<3% of cases), heritable, form of AD. The causes of the far more prevalent, sporadic, form are unknown, though recent work has implicated environmental factors, prominently including stress, as promoting AD pathogenesis. For example, recent epidemiological studies indicate that individuals prone to experience psychological distress or anxiety are at substantially greater risk to develop AD as age-matched controls that score low on this dimension. The overarching hypothesis of this proposal is that chronic stress exposure in humans confers increased risk of AD due to stress-associated alterations in the cortical and hippocampal CRF signaling systems. Based on our preliminary data, we propose that a potential mechanism underlying this stress-AD relationship is the modulation of A? by CRFR1 activation.

Public Health Relevance

Stress has been identified as a risk factor for developing Alzheimer's disease (AD). Our work in animals has identified signaling through a major stress mediator, the type 1 corticotropin-releasing factor receptor (CRFR1), as contributing to the development of both defining hallmarks of AD pathology, ?-amyloid (A?) plaque formation and tau phosphorylation/ aggregation. Here we propose to determine the specific changes that occur in the human AD brain and a rodent model. We will also determine the impact of protracted stress exposure and drugs that interfere with the CRF system to inform on the mechanisms of CRF involvement in AD.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
Project #
Application #
Study Section
Neurobiology D (NURD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
VA San Diego Healthcare System
San Diego
United States
Zip Code
Rockenstein, Edward; Ostroff, Gary; Dikengil, Fusun et al. (2018) Combined Active Humoral and Cellular Immunization Approaches for the Treatment of Synucleinopathies. J Neurosci 38:1000-1014
Chen, Xu-Qiao; Fang, Fang; Florio, Jazmin B et al. (2018) T-complex protein 1-ring complex enhances retrograde axonal transport by modulating tau phosphorylation. Traffic 19:840-853
Kim, Changyoun; Spencer, Brian; Rockenstein, Edward et al. (2018) Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating ?-synuclein transmission and neuroinflammation. Mol Neurodegener 13:43
Pottier, Cyril; Zhou, Xiaolai; Perkerson 3rd, Ralph B et al. (2018) Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Lancet Neurol 17:548-558
Ngolab, Jennifer; Trinh, Ivy; Rockenstein, Edward et al. (2017) Brain-derived exosomes from dementia with Lewy bodies propagate ?-synuclein pathology. Acta Neuropathol Commun 5:46
Reilly, Patrick; Winston, Charisse N; Baron, Kelsey R et al. (2017) Novel human neuronal tau model exhibiting neurofibrillary tangles and transcellular propagation. Neurobiol Dis 106:222-234
You, Jason C; Muralidharan, Kavitha; Park, Jin W et al. (2017) Epigenetic suppression of hippocampal calbindin-D28k by ?FosB drives seizure-related cognitive deficits. Nat Med 23:1377-1383
El-Agnaf, Omar; Overk, Cassia; Rockenstein, Edward et al. (2017) Differential effects of immunotherapy with antibodies targeting ?-synuclein oligomers and fibrils in a transgenic model of synucleinopathy. Neurobiol Dis 104:85-96
Spencer, Brian; Valera, Elvira; Rockenstein, Edward et al. (2017) Anti-?-synuclein immunotherapy reduces ?-synuclein propagation in the axon and degeneration in a combined viral vector and transgenic model of synucleinopathy. Acta Neuropathol Commun 5:7
Le, Michelle H; Weissmiller, April M; Monte, Louise et al. (2016) Functional Impact of Corticotropin-Releasing Factor Exposure on Tau Phosphorylation and Axon Transport. PLoS One 11:e0147250