Abstract
Background
Multiple pathogeneses are involved in Alzheimer's disease (AD), such as amyloid-β
accumulation, neuroinflammation, and oxidative stress. The pathological impact of
chronic cerebral hypoperfusion on Alzheimer's disease is still poorly understood.
Methods
APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid
constrictors for slowly progressive chronic cerebral hypoperfusion (CCH). The effects
of the administration of Twendee X (TwX) were evaluated by behavioral analysis, immunohistochemical
analysis, and immunofluorescent histochemistry.
Results
In the present study, chronic cerebral hypoperfusion, which is commonly found in aged
Alzheimer's disease, significantly exacerbated motor dysfunction of APP23 mice from
5 months and cognitive deficit from 8 months of age, as well as neuronal loss, extracellular
amyloid-β plaque and intracellular oligomer formations, and amyloid angiopathy at
12 months. Severe upregulations of oxidative markers and inflammatory markers were
found in the cerebral cortex, hippocampus, and thalamus at 12 months. Twendee X treatment
(20 mg/kg/d, from 4.5 to 12 months) substantially rescued the cognitive deficit and
reduced the above amyloid-β pathology and neuronal loss, alleviated neuroinflammation
and oxidative stress.
Conclusions
The present findings suggested a potential therapeutic benefit of Twendee X for Alzheimer's
disease with chronic cerebral hypoperfusion.
Key Words
Abbreviations:
ACs (ameriod constrictors), AD (Alzheimer's disease), Aβ (amyloid-β), BCCAs (bilateral common carotid arteries), BSA (bovine serum albumin), CBF (cerebral blood flow), CCH (chronic cerebral hypoperfusion), CTX (cortex), DG (dentate gyrus), HI (hippocampus), M (months), PBS (phosphate-buffered saline), PFA (paraformaldehyde), Sub (subiculum), TH (thalamus), TwX (Twendee X), WT (wild type)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Stroke and Cerebrovascular DiseasesAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Characteristic features of cognitive, affective and daily living functions of late-elderly dementia.Geriatr Gerontol Int. 2016; 16: 458-465
- Alzheimer's disease: genes, proteins, and therapy.Physiol Rev. 2001; 81: 741-766
- A systemic view of Alzheimer disease–insights from amyloid-β metabolism beyond the brain.Nat Rev Neurol. 2017; 13: 703
- Oxidative damage in Alzheimer's disease: the metabolic dimension.Int J Dev Neurosci. 2000; 18: 417-421
- Inflammation and oxidative stress: the molecular connectivity between insulin resistance, obesity, and Alzheimer's disease.Mediators Inflamm. 2015; 2015105828
- Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia.Clin Sci. 2017; 131: 2451-2468
- Strong impact of chronic cerebral hypoperfusion on neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling in Alzheimer's disease model mouse.J Alzheimers Dis. 2016; 52: 113-126
- Chronic cerebral hypoperfusion accelerates Alzheimer's disease pathology with cerebrovascular remodeling in a novel mouse model.J Alzheimers Dis. 2016; 53: 893-905
- Neuroprotective effects of a novel antioxidant mixture Twendee X in mouse stroke model.J Stroke Cerebrovasc Dis. 2017; 26: 1191-1196
- Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology.Proc Natl Acad Sci U S A. 1997; 94: 13287-13292
- Intrathecal injection of epidermal growth factor and fibroblast growth factor 2 promotes proliferation of neural precursor cells in the spinal cords of mice with mutant human SOD1 gene.J Neurosci Res. 2006; 84: 980-992
- Atorvastatin and pitavastatin improve cognitive function and reduce senile plaque and phosphorylated tau in aged APP mice.Brain Res. 2011; 1371: 161-170
- (-)-SCR1693 protects against memory impairment and hippocampal damage in a chronic cerebral hypoperfusion rat model.Sci Rep. 2016; 6: 28908
- Hippocampal CA3-region is crucial for acquisition and memory consolidation in Morris water maze task in mice.Behav Brain Res. 2004; 154: 365-374
- NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.Nature. 2013; 493: 674-678
- TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study.MedGenMed. 2006; 8: 25
- Alzheimer disease and oxidative stress.J Biomed Biotechnol. 2002; 2: 120-123
- Oxidative imbalance in Alzheimer's disease.Mol Neurobiol. 2005; 31: 205-217
- Role of oxidative stress in the progression of Alzheimer's disease.J Alzheimers Dis. 2010; 19: 341-353
- Oxidative stress and inflammation: what polyphenols can do for us?.Oxid Med Cell Longev. 2016; 2016 (Epub 2016 Sep 22)7432797
- Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF.Oxid Med Cell Longev. 2015; 2015 (Epub 2015 Mar 5)610813https://doi.org/10.1155/2015/610813
- Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways.J Neurochem. 2005; 92: 628-636
- Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice.Nutr Neurosci. 2009; 12: 203-218
- Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer's disease.J Alzheimers Dis. 2011; 27: 211-223
- The possible role of antioxidant vitamin C in Alzheimer's disease treatment and prevention.Am J Alzheimers Dis Other Demen. 2013; 28: 120-125
Inufusa H. Composition for protection against cell-damaging effects, US Patent: 9089548 B2. Issued date July 28th, 2015.
Article info
Publication history
Published online: April 24, 2019
Accepted:
March 10,
2019
Received in revised form:
March 4,
2019
Received:
January 9,
2019
Footnotes
Financial Disclosure: This work was partly supported by a Grant-in-Aid for Scientific Research (B) 17H04196, (C) 17K10827 and Challenging Research 15K15527, and by Grants-in-Aid from the Research Committees (Mizusawa H, Nishizawa M, Sasaki H, and Aoki M) from the Ministry of Health, Labour and Welfare, Japan.
Identification
DOI: https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.03.029
Copyright
© 2019 Elsevier Inc. All rights reserved.
