Behavioral effects of Rho GTPase modulation in a model of Alzheimer's disease

Musilli, Marco; Nicolia, Vincenzina; Borrelli, Sonia; Scarpa, Sigfrido; Diana, Giovanni

doi:10.1016/j.bbr.2012.09.043

Cited by 35 publications

(27 citation statements)

References 44 publications

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“…Previous papers suggested the efficacy of CNF1 in animal models of intellectual disability and Alzheimer's disease (De Filippis et al, 2013;Musilli et al, 2013). The present work indicates that the modulation of Rho GTPases be also effective in reversing the longstanding damage of the nigrostriatal pathway.…”

Section: Discussionsupporting

confidence: 56%

Therapeutic effects of the Rho GTPase modulator CNF1 in a model of Parkinson’s disease

et al. 2016

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Section: Discussionsupporting

confidence: 56%

Therapeutic effects of the Rho GTPase modulator CNF1 in a model of Parkinson’s disease

et al. 2016

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“…An overexpression of Rab5 or Rab7, small GTPases that function in vesicle fusion for early and late endosomes, respectively, significantly accelerates Aβ endocytic trafficking to the lysosomes [117]. A potential role for Rho-GTPase has also been elucidated in TgCRND8, a transgenic mouse model that rapidly deposits human Aβ [118]. However, as this compartment is known to be rich in other acid proteases, nascent Aβ may also undergo degradation at this location.…”

Section: Cellular Maintenance and Aβ Regulationmentioning

confidence: 99%

Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

Baranello¹,

Bharani²,

Padmaraju³

et al. 2015

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Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer’s disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin-2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβ turnover.

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“…29) Memory dysfunction is mainly associated with loss of cholinergic neurons in several regions of the brain, especially the basal forebrain and hippocampal CA1 region. [30][31][32] Immunohistochemical results for ChAT expression indicated that significant loss of cholinergic neurons occurred in the hippocampal CA1 regions of rats with diabetes and CCH. Moreover, hippocampal ChAT levels were restored after CM treatment, suggesting that CM has neuroprotective effects on the cholinergic system.…”

Section: 25)mentioning

confidence: 99%

Cinepazide Maleate Improves Cognitive Function and Protects Hippocampal Neurons in Diabetic Rats with Chronic Cerebral Hypoperfusion

Zhang

et al. 2017

Biological & Pharmaceutical Bulletin

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To determine the combined effect of type 2 diabetes (T2D) and chronic cerebral hypoperfusion (CCH) on learning and spatial memory, we developed a rat model of CCH by permanent occlusion of bilateral common carotid arteries (2-vessel occlusion (2VO)) in high-fat diet (HFD)-fed rats injected with low-dose streptozotocin (STZ). Furthermore, we examined the effect of cinepazide maleate (CM) on cognitive deficits and brain damage in this rat model. Rats were maintained on HFD for 6 weeks and then injected with 35 mg/kg STZ to induce T2D. Sham or 2VO surgery was performed in non-diabetic or diabetic (DM) rats to obtain four groups: blank, DM, CCH, and DM-CCH groups. Cognitive function was tested by the Morris water maze (MWM) test. To determine the effects of the vasodilator cinepazide maleate (CM) on cognitive deficits and brain damage, DM-CCH rats were administered with 10 mg/kg CM or saline daily for 14 d. Neuronal damage in DM-CCH rats was associated with increased expression of glial fibrillary acidic protein (GFAP) and β-secretase 1 (BACE1), but decreased expression of choline acetyltransferase (ChAT). Moreover, the levels of all these proteins were significantly alleviated by CM treatment. These results suggest that T2D exacerbated CCH-induced brain damage and cognitive impairment, and CM ameliorated these effects.Key words diabetes; chronic cerebral hypoperfusion; cognitive impairment; cinepazide maleate Chronic cerebral hypoperfusion (CCH) is thought to be an important factor contributing to cognitive decline, both in aging and in age-related neurological disorders.1-3) The severity of memory dysfunction and the decline in cerebral blood flow are strongly correlated in disorders, such as Alzheimer's disease (AD), vascular dementia, and stroke.4,5) Diabetes is one of the fastest growing epidemics worldwide and diabetic patients are at a high risk for development of cognitive impairment or dementia. 6) Moreover, diabetes is often associated with CCH, and can further aggravate neurodegeneration.Permanent bilateral occlusion of both common carotid arteries (or 2-vessel occlusion, 2VO) is a widely used rodent model of CCH. As the model mimics several features of human AD and vascular dementia, it is used to investigate the consequences of hypoperfusion on cerebral blood flow, cognitive ability, and histopathology in these neurological disorders.2,7) Progressive cognitive impairment has been reported after 2VO in rats, 2,[8][9][10][11] and behavioral changes resulting from cognitive impairment are associated with delayed loss of neurons in the hippocampal CA1 region, a feature commonly observed in human aging and dementia.2) CA1 cell loss is characterized by gliosis, cholinergic dysfunction, 12) and activation of β-secretase 1 (BACE1).13) Consistent memory impairment after 2VO in rats occurs in the chronic phase of the ischemic event, i.e., up to 3 months after surgery, and not within 7 d, as assessed by water maze and object recognition tasks. 14)Cinepazide maleate (CM) is a calcium-channel blocker with vasodilato...

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Behavioral effects of Rho GTPase modulation in a model of Alzheimer's disease

Cited by 35 publications

References 44 publications

Therapeutic effects of the Rho GTPase modulator CNF1 in a model of Parkinson’s disease

Therapeutic effects of the Rho GTPase modulator CNF1 in a model of Parkinson’s disease

Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

Cinepazide Maleate Improves Cognitive Function and Protects Hippocampal Neurons in Diabetic Rats with Chronic Cerebral Hypoperfusion

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