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

Overview

Journal J Alzheimers Dis

Publisher Sage Publications

Specialties Geriatrics
Neurology

Date 2015 Feb 21

PMID 25697705

Citations 22

Authors

Shannon N Campbell

Cheng Zhang

Allyson D Roe

Nickey Lee

Kathleen U Lao

Louise Monte

Michael C Donohue

Robert A Rissman

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

The Aggravating Role of Failing Neuropeptide Networks in the Development of Sporadic Alzheimer's Disease.

Jaszberenyi M, Thurzo B, Jayakumar A, Schally A Int J Mol Sci. 2024; 25(23).

PMID: 39684795 PMC: 11641508. DOI: 10.3390/ijms252313086.

Anxiety and Alzheimer's disease pathogenesis: focus on 5-HT and CRF systems in 3xTg-AD and TgF344-AD animal models.

Reyna N, Clark B, Hamilton D, Pentkowski N Front Aging Neurosci. 2023; 15:1251075.

PMID: 38076543 PMC: 10699143. DOI: 10.3389/fnagi.2023.1251075.

Emerging Alzheimer's disease therapeutics: promising insights from lipid metabolism and microglia-focused interventions.

Tobeh N, Bruce K Front Aging Neurosci. 2023; 15:1259012.

PMID: 38020773 PMC: 10630922. DOI: 10.3389/fnagi.2023.1259012.

Novel systemic delivery of a peptide-conjugated antisense oligonucleotide to reduce α-synuclein in a mouse model of Alzheimer's disease.

Leitao A, Ahammad R, Spencer B, Wu C, Masliah E, Rissman R Neurobiol Dis. 2023; 186:106285.

PMID: 37690676 PMC: 10584037. DOI: 10.1016/j.nbd.2023.106285.

Hippocampal Reduction of α-Synuclein via RNA Interference Improves Neuropathology in Alzheimer's Disease Mice.

Leitao A, Spencer B, Sarsoza F, Ngolab J, Amalraj J, Masliah E J Alzheimers Dis. 2023; 95(1):349-361.

PMID: 37522208 PMC: 10578232. DOI: 10.3233/JAD-230232.

References

Swaab D, Bao A, Lucassen P . The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev. 2005; 4(2):141-94. DOI: 10.1016/j.arr.2005.03.003. View

Feng Q, Cheng B, Yang R, Sun F, Zhu C . Dynamic changes of phosphorylated tau in mouse hippocampus after cold water stress. Neurosci Lett. 2005; 388(1):13-6. DOI: 10.1016/j.neulet.2005.06.022. View

Ownby R, Crocco E, Acevedo A, John V, Loewenstein D . Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006; 63(5):530-8. PMC: 3530614. DOI: 10.1001/archpsyc.63.5.530. View

Winton M, Lee E, Sun E, Wong M, Leight S, Zhang B . Intraneuronal APP, not free Aβ peptides in 3xTg-AD mice: implications for tau versus Aβ-mediated Alzheimer neurodegeneration. J Neurosci. 2011; 31(21):7691-9. PMC: 3118598. DOI: 10.1523/JNEUROSCI.6637-10.2011. View

Albasser M, Amin E, Iordanova M, Brown M, Pearce J, Aggleton J . Separate but interacting recognition memory systems for different senses: the role of the rat perirhinal cortex. Learn Mem. 2011; 18(7):435-43. PMC: 3125609. DOI: 10.1101/lm.2132911. View

Albasser M, Amin E, Iordanova M, Brown M, Pearce J, Aggleton J . Perirhinal cortex lesions uncover subsidiary systems in the rat for the detection of novel and familiar objects. Eur J Neurosci. 2011; 34(2):331-42. PMC: 3170480. DOI: 10.1111/j.1460-9568.2011.07755.x. View

Green K, Billings L, Roozendaal B, McGaugh J, LaFerla F . Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer's disease. J Neurosci. 2006; 26(35):9047-56. PMC: 6675335. DOI: 10.1523/JNEUROSCI.2797-06.2006. View

Csernansky J, Dong H, Fagan A, Wang L, Xiong C, Holtzman D . Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am J Psychiatry. 2006; 163(12):2164-9. PMC: 1780275. DOI: 10.1176/ajp.2006.163.12.2164. View

Hartig W, Stieler J, Boerema A, Wolf J, Schmidt U, Weissfuss J . Hibernation model of tau phosphorylation in hamsters: selective vulnerability of cholinergic basal forebrain neurons - implications for Alzheimer's disease. Eur J Neurosci. 2007; 25(1):69-80. DOI: 10.1111/j.1460-9568.2006.05250.x. View

10.

Ikeda Y, Ishiguro K, Fujita S . Ether stress-induced Alzheimer-like tau phosphorylation in the normal mouse brain. FEBS Lett. 2007; 581(5):891-7. DOI: 10.1016/j.febslet.2007.01.064. View

11.

Landfield P, Blalock E, Chen K, Porter N . A new glucocorticoid hypothesis of brain aging: implications for Alzheimer's disease. Curr Alzheimer Res. 2007; 4(2):205-12. PMC: 3573879. DOI: 10.2174/156720507780362083. View

12.

Dere E, Huston J, de Souza Silva M . The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neurosci Biobehav Rev. 2007; 31(5):673-704. DOI: 10.1016/j.neubiorev.2007.01.005. View

13.

Rissman R, Lee K, Vale W, Sawchenko P . Corticotropin-releasing factor receptors differentially regulate stress-induced tau phosphorylation. J Neurosci. 2007; 27(24):6552-62. PMC: 6672442. DOI: 10.1523/JNEUROSCI.5173-06.2007. View

14.

Kang J, Cirrito J, Dong H, Csernansky J, Holtzman D . Acute stress increases interstitial fluid amyloid-beta via corticotropin-releasing factor and neuronal activity. Proc Natl Acad Sci U S A. 2007; 104(25):10673-8. PMC: 1965571. DOI: 10.1073/pnas.0700148104. View

15.

Justice N, Yuan Z, Sawchenko P, Vale W . Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice: implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system. J Comp Neurol. 2008; 511(4):479-96. PMC: 2597626. DOI: 10.1002/cne.21848. View

16.

Lee K, Kim J, Seo J, Kim T, Im J, Baek I . Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress. J Neurochem. 2008; 108(1):165-75. DOI: 10.1111/j.1471-4159.2008.05769.x. View

17.

Thangavel R, Van Hoesen G, Zaheer A . The abnormally phosphorylated tau lesion of early Alzheimer's disease. Neurochem Res. 2008; 34(1):118-23. DOI: 10.1007/s11064-008-9701-1. View

18.

Kivipelto M, Rovio S, Ngandu T, Kareholt I, Eskelinen M, Winblad B . Apolipoprotein E epsilon4 magnifies lifestyle risks for dementia: a population-based study. J Cell Mol Med. 2008; 12(6B):2762-71. PMC: 3828889. DOI: 10.1111/j.1582-4934.2008.00296.x. View

19.

Dong H, Csernansky J . Effects of stress and stress hormones on amyloid-beta protein and plaque deposition. J Alzheimers Dis. 2009; 18(2):459-69. PMC: 2905685. DOI: 10.3233/JAD-2009-1152. View

20.

Vassar R, Kovacs D, Yan R, Wong P . The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential. J Neurosci. 2009; 29(41):12787-94. PMC: 2879048. DOI: 10.1523/JNEUROSCI.3657-09.2009. View