Targeting neuroinflammation in the treatment and prevention of
                        Alzheimer's disease

Zenaro, Elena; Constantin, Gabriela

doi:10.1358/dof.2017.042.01.2564104

Cited by 4 publications

(7 citation statements)

References 279 publications

(437 reference statements)

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“…LFA-1 integrin blockade or neutrophil depletion at the inception AD had a significant ability to decrease memory deficits and other neuropathological hallmarks in AD-like mouse models. 125 This clearly demonstrates the role of neutrophils in the induction of cognitive dysfunction. Also, at the earlier stages of the disease, brief suspension of neutrophils had an effective long-term effect on older animals, which shows that neutrophils are indeed vital for the development of a chronic disorder.…”

Section: ■ Disease Modifying Strategiesmentioning

confidence: 81%

Molecular Pathogenesis and Interventional Strategies for Alzheimer’s Disease: Promises and Pitfalls

Bhute

Sarmah

Datta

et al. 2020

ACS Pharmacol. Transl. Sci.

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Alzheimer’s disease (AD) is a debilitating disorder characterized by age-related dementia, which has no effective treatment to date. β-Amyloid depositions and hyperphosphorylated tau proteins are the main pathological hallmarks, along with oxidative stress, N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity, and low levels of acetylcholine. Current pharmacotherapy for AD only provides symptomatic relief and limited improvement in cognitive functions. Many molecules have been explored that show promising outcomes in AD therapy and can regulate cellular survival through different pathways. To have a vivid approach to strategize the treatment regimen, AD physiopathology should be better explained considering diverse etiological factors in conjunction with biochemical disturbances. This Review attempts to discuss different disease modification approaches and address the novel therapeutic targets of AD that might pave the way for new drug discovery using the well-defined targets for therapy of the disease.

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Section: ■ Disease Modifying Strategiesmentioning

confidence: 81%

Molecular Pathogenesis and Interventional Strategies for Alzheimer’s Disease: Promises and Pitfalls

Bhute

Sarmah

Datta

et al. 2020

ACS Pharmacol. Transl. Sci.

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“…Furthermore, upregulation of the pro-inflammatory chemokine CCL3 was detected in both CSF and serum of App NL–G–F compared to WT mice. CCL3 is said to exert neuronal damage and deleterious effects on synaptic plasticity and learning performance by contributing to CNS inflammation by promoting migration of T-lymphocytes into the brain ( Marciniak et al, 2015 ; Zenaro and Constantin, 2017 ; Martin and Delarasse, 2018 ). The induction of (neuro-) inflammatory processes is one hallmark of the AD-like pathology in App NL–G–F KI mice, as summarized by the developers of the model ( Saito and Saido, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

The Roles of Long-Term Hyperhomocysteinemia and Micronutrient Supplementation in the AppNL–G–F Model of Alzheimer’s Disease

Nieraad

Bruin

Arne

et al. 2022

Front. Aging Neurosci.

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A causal contribution of hyperhomocysteinemia to cognitive decline and Alzheimer’s disease (AD), as well as potential prevention or mitigation of the pathology by dietary intervention, have frequently been subjects of controversy. In the present in vivo study, we attempted to further elucidate the impact of elevated homocysteine (HCys) and homocysteic acid (HCA) levels, induced by dietary B-vitamin deficiency, and micronutrient supplementation on AD-like pathology, which was simulated using the amyloid-based AppNL–G–F knock-in mouse model. For this purpose, cognitive assessment was complemented by analyses of ex vivo parameters in whole blood, serum, CSF, and brain tissues from the mice. Furthermore, neurotoxicity of HCys and HCA was assessed in a separate in vitro assay. In confirmation of our previous study, older AppNL–G–F mice also exhibited subtle phenotypic impairment and extensive cerebral amyloidosis, whereas dietary manipulations did not result in significant effects. As revealed by proximity extension assay-based proteome analysis, the AppNL–G–F genotype led to an upregulation of AD-characteristic neuronal markers. Hyperhomocysteinemia, in contrast, indicated mainly vascular effects. Overall, since there was an absence of a distinct phenotype despite both a significant amyloid-β burden and serum HCys elevation, the results in this study did not corroborate the pathological role of amyloid-β according to the “amyloid hypothesis,” nor of hyperhomocysteinemia on cognitive performance. Nevertheless, this study aided in further characterizing the AppNL–G–F model and in elucidating the role of HCys in diverse biological processes. The idea of AD prevention with the investigated micronutrients, however, was not supported, at least in this mouse model of the disease.

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“…Chronic low-grade inflammation is thought to play a key role in the development of AD neuropathology. Previous studies of inflammation in AD have focused mainly on the activation of microglia 3 . However, several recent studies have shown that a dysfunctional blood–brain barrier associated with vascular inflammation and leukocyte migration into the brain contribute to the pathogenesis of AD 3–5 .…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies of inflammation in AD have focused mainly on the activation of microglia 3 . However, several recent studies have shown that a dysfunctional blood–brain barrier associated with vascular inflammation and leukocyte migration into the brain contribute to the pathogenesis of AD 3–5 . In particular, we and others have shown that circulating leukocytes adhere to the endothelium in cerebral vessels and migrate into the brain parenchyma in AD patients and in transgenic animals with AD-like disease 3–7 .…”

Section: Introductionmentioning

confidence: 99%

“…However, several recent studies have shown that a dysfunctional blood–brain barrier associated with vascular inflammation and leukocyte migration into the brain contribute to the pathogenesis of AD 3–5 . In particular, we and others have shown that circulating leukocytes adhere to the endothelium in cerebral vessels and migrate into the brain parenchyma in AD patients and in transgenic animals with AD-like disease 3–7 . Our recent data show that neutrophils (the most abundant leukocytes in the human circulation) adhere in cerebral vessels and migrate into the AD brain.…”

Section: Introductionmentioning

confidence: 99%

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Blockade of α4 integrins reduces leukocyte–endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer’s disease

Pietronigro

Zenaro

Bianca

et al. 2019

Sci Rep

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Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline associated with the deposition of amyloid-β (Aβ) plaques, hyperphosphorylation of tau protein, and neuronal loss. Vascular inflammation and leukocyte trafficking may contribute to AD pathogenesis, and a better understanding of these inflammation mechanisms could therefore facilitate the development of new AD therapies. Here we show that T cells extravasate in the proximity of cerebral VCAM-1 + vessels in 3xTg-AD transgenic mice, which develop both Aβ and tau pathologies. The counter-ligand of VCAM-1 – α4β1 integrin, also known as very late antigen-4 (VLA-4) – was more abundant on circulating CD4 + T cells and was also expressed by a significant proportion of blood CD8 + T cells and neutrophils in AD mice. Intravital microscopy of the brain microcirculation revealed that α4 integrins control leukocyte–endothelial interactions in AD mice. Therapeutic targeting of VLA-4 using antibodies that specifically block α4 integrins improved the memory of 3xTg-AD mice compared to an isotype control. These antibodies also reduced neuropathological hallmarks of AD, including microgliosis, Aβ load and tau hyperphosphorylation. Our results demonstrate that α4 integrin-dependent leukocyte trafficking promotes cognitive impairment and AD neuropathology, suggesting that the blockade of α4 integrins may offer a new therapeutic strategy in AD.

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Targeting neuroinflammation in the treatment and prevention of Alzheimer's disease

Cited by 4 publications

References 279 publications

Molecular Pathogenesis and Interventional Strategies for Alzheimer’s Disease: Promises and Pitfalls

Molecular Pathogenesis and Interventional Strategies for Alzheimer’s Disease: Promises and Pitfalls

The Roles of Long-Term Hyperhomocysteinemia and Micronutrient Supplementation in the AppNL–G–F Model of Alzheimer’s Disease

Blockade of α4 integrins reduces leukocyte–endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer’s disease

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