Corticotrophin Releasing Factor Accelerates Neuropathology and Cognitive Decline in a Mouse Model of Alzheimer's Disease

Dong, Hongxin; Murphy, Keely M.; Meng, Liping; Montalvo-Ortiz, Janitza L.; Zeng, Ziling; Kolber, Benedict J.; Zhang, Shanshan; Muglia, Louis J.; Csernansky, John G.

doi:10.3233/jad-2011-111328

Cited by 54 publications

(42 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The effect of a pituitary microadenoma on brain Aβ flux is unknown. While acute and chronic overexpression of CRH have been shown to increase levels of soluble Aβ and accelerate amyloid pathology in transgenic mouse models of AD, 35, 36 we do not anticipate that the administration of CRH used in this experiment would alter normal brain Aβ flux over the time course of our sample collections (10 minutes). Further, samples collected before and after CRH administration showed no significant change in Aβ levels (p=0.81).…”

Section: Discussionmentioning

confidence: 93%

Amyloid‐β efflux from the central nervous system into the plasma

Roberts

Elbert

Kasten

et al. 2014

Annals of Neurology

229

161

View full text Add to dashboard Cite

Objective The aim of this study was to measure the flux of amyloid-β (Aβ) across the human cerebral capillary bed in order to determine if transport into the blood is a significant mechanism of clearance for Aβ produced in the central nervous system (CNS). Methods Time-matched blood samples were simultaneously collected from a cerebral vein (including the sigmoid sinus, inferior petrosal sinus, and the internal jugular vein), femoral vein, and radial artery of patients undergoing Inferior Petrosal Sinus Sampling (IPSS). For each plasma sample, Aβ concentration was assessed by three assays and the venous to arterial Aβ concentration ratios were determined. Results Aβ concentration was increased by ~7.5% in venous blood leaving the CNS capillary bed compared to arterial blood, indicating efflux from the CNS into the peripheral blood (p < 0.0001). There was no difference in peripheral venous Aβ concentration compared to arterial blood concentration. Interpretation Our results are consistent with clearance of CNS-derived Aβ into the venous blood supply with no increase from a peripheral capillary bed. Modeling these results suggests that direct transport of Aβ across the blood-brain barrier accounts for ~25% of Aβ clearance, and reabsorption of cerebrospinal fluid Aβ accounts for ~25% of the total CNS Aβ clearance in humans.

show abstract

Section: Discussionmentioning

confidence: 93%

Amyloid‐β efflux from the central nervous system into the plasma

Roberts

Elbert

Kasten

et al. 2014

Annals of Neurology

229

161

View full text Add to dashboard Cite

show abstract

“…It has been hypothesized that these changes result from changes in a specific CRF binding protein [35], which is expressed in brain [36] and can reversibly neutralize CRF bioactivity. Furthermore, studies in rodent models demonstrate that CRF overexpression can lead to tau phosphorylation and aggregation, brain atrophy, and cognitive impairment [13, 20–22]. …”

Section: Discussionmentioning

confidence: 99%

Impact of CRFR1 Ablation on Amyloid-β Production and Accumulation in a Mouse Model of Alzheimer's Disease

Campbell

Zhang

Roe

et al. 2015

JAD

View full text Add to dashboard Cite

Stress exposure and the corticotropin-releasing factor (CRF) system have been implicated as mechanistically involved in both Alzheimer’s disease (AD) and associated rodent models. In particular, the major stress receptor, CRF receptor type 1 (CRFR1), modulates cellular activity in many AD-relevant brain areas, and has been demonstrated to impact both tau phosphorylation and amyloid-β (Aβ) pathways. The overarching goal of our laboratory is to develop and characterize agents that impact the CRF signaling system as disease-modifying treatments for AD. In the present study, we developed a novel transgenic mouse to determine whether partial or complete ablation of CRFR1 was feasible in an AD transgenic model and whether this type of treatment could impact Aβ pathology. Double transgenic AD mice (PSAPP) were crossed to mice null for CRFR1; resultant CRFR1 heterozygous (PSAPP-R1+/−) and homozygous (PSAPP-R1−/−) female offspring were used at 12 months of age to examine the impact of CRFR1 disruption on the severity of AD Aβ levels and pathology. We found that both PSAPP-R1+/− and PSAPP-R1−/− had significantly reduced Aβ burden in the hippocampus, insular, rhinal, and retrosplenial cortices. Accordingly, we observed dramatic reductions in Aβ peptides and AβPP-CTFs, providing support for a direct relationship between CRFR1 and Aβ production pathways. In summary, our results suggest that interference of CRFR1 in an AD model is tolerable and is efficacious in impacting Aβ neuropathology.

show abstract

“…Cortical tissue (n=5 mice each group) was homogenized and subjected to Western Blotting 17, 21 . Immunoblots from CRF-OE cortex were probed with a monocolonal antibody to assess paired helical filament (PHF-1, 1:1,000, V. Lee, Univ.…”

Section: Methodsmentioning

confidence: 99%

Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer’s disease-related signaling

et al. 2016

View full text Add to dashboard Cite

Several neuropsychiatric and neurodegenerative disorders share stress as a risk factor and are more prevalent in women than men. Corticotropin releasing factor (CRF) orchestrates the stress response and excessive CRF is thought to contribute to the pathophysiology of these diseases. We previously found that the CRF1 receptor (CRF1) is sex-biased whereby coupling to its GTP-binding protein, Gs, is greater in females, while β-arrestin-2 coupling is greater in males. This study used a phosphoproteomic approach in CRF-overexpressing mice (CRF-OE) to test the proof of principle that when CRF is in excess, sex-biased CRF1 coupling translates into divergent cell signaling that is expressed as different brain phosphoprotein profiles. Cortical phosphopeptides that distinguished female and male CRF-OE mice were overrepresented in unique pathways that were consistent with Gs-dependent signaling in females and β-arrestin-2 signaling in males. Notably, phosphopeptides that were more abundant in female CRF-OE mice were overrepresented in an Alzheimer's disease (AD) pathway. Phosphoproteomic results were validated by demonstrating that CRF overexpression in females was associated with increased tau phosphorylation and, in a mouse model of AD pathology, phosphorylation of β-secretase, the enzyme involved in formation of amyloid β. These females exhibited increased formation of amyloid β plaques and cognitive impairments relative to males. Collectively, the findings are consistent with a mechanism whereby the excess CRF that characterizes stress-related diseases initiates distinct cellular processes in male and female brains, as a result of sex biased CRF1 signaling. Promotion of AD-related signaling pathways through this mechanism may contribute to female vulnerability to AD.

show abstract

Corticotrophin Releasing Factor Accelerates Neuropathology and Cognitive Decline in a Mouse Model of Alzheimer's Disease

Cited by 54 publications

References 62 publications

Amyloid‐β efflux from the central nervous system into the plasma

Amyloid‐β efflux from the central nervous system into the plasma

Impact of CRFR1 Ablation on Amyloid-β Production and Accumulation in a Mouse Model of Alzheimer's Disease

Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer’s disease-related signaling

Contact Info

Product

Resources

About