Adalimumab improves cognitive impairment, exerts neuroprotective effects and attenuates neuroinflammation in an Aβ1-40-injected mouse model of Alzheimer's disease

Park, Jiae; Lee, Sun-Young; Shon, Jeeheun; Kim, Koeun; Kim, Kyung-Ah; Lee, Boo-Yong; Oh, Seung-Hun; Kim, Nam Keun

doi:10.1016/j.jcyt.2019.04.054

Cited by 41 publications

(32 citation statements)

References 68 publications

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“…These drugs have been tested on AD rodent models via central and peripheral routes of administration [ 345 , 350 ]. Adalimumab significantly attenuated neuronal damage and neuroinflammation, decreased beta secretase-1 protein expression and Aβ1-40 plaques, and improved cognitive functions in Aβ1-40-injected mice [ 351 , 352 ], suggesting possible clinically meaningful outcomes in patients with AD. Indeed, patients with rheumatic disorders that are treated with TNF-blocking agents have a lower risk for developing AD [ 353 ].…”

Section: Possible Intervention For Neuroinflammation In Admentioning

confidence: 99%

Neuroinflammation in Alzheimer’s Disease

et al. 2021

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Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.

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Section: Possible Intervention For Neuroinflammation In Admentioning

confidence: 99%

Neuroinflammation in Alzheimer’s Disease

et al. 2021

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“…Adalimumab treatment leads to significantly attenuated neuronal damage and neuroinflammation, decreased beta secretase-1 protein expression and Aβ1-40 plaques, and to improvement of cognitive functions in Aβ1-40-injected mice (Park et al, 2019;Anwar and Rivest, 2020), supplying a rationale for a hypothesis of clinically meaningful outcomes in patients with AD.…”

Section: Adalimumabmentioning

confidence: 99%

Repositioning of Immunomodulators: A Ray of Hope for Alzheimer’s Disease?

et al. 2020

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Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder characterized by cognitive decline and by the presence of amyloid β plaques and neurofibrillary tangles in the brain. Despite recent advances in understanding its pathophysiological mechanisms, to date, there are no disease-modifying therapeutic options, to slow or halt the evolution of neurodegenerative processes in AD. Current pharmacological treatments only transiently mitigate the severity of symptoms, with modest or null overall improvement. Emerging evidence supports the concept that AD is affected by the impaired ability of the immune system to restrain the brain’s pathology. Deep understanding of the relationship between the nervous and the immune system may provide a novel arena to develop effective and safe drugs for AD treatment. Considering the crucial role of inflammatory/immune pathways in AD, here we discuss the current status of the immuno-oncological, immunomodulatory and anti-TNF-α drugs which are being used in preclinical studies or in ongoing clinical trials by means of the drug-repositioning approach.

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“…Our results confirm and extend those previous reports connecting axonal damage, RGC loss and TNFα. Our strategy differs from previous works targeting TNFα (Roh et al, 2012; Tse et al, 2018; Park et al, 2019) in that instead of blocking TNFα using decoy-receptors, we have used an antagonist of the TNFα/TNFR1 signaling pathway. R7050 inhibits the endocytosis of the TNF-α/TNFR1 multiprotein complex (Gururaja et al, 2007), thus blocking the extrinsic pathway of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Systemic and Intravitreal Antagonism of the TNFR1 Signaling Pathway Delays Axotomy-Induced Retinal Ganglion Cell Loss

et al. 2019

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Here, we have blocked the signaling pathway of tumor necrosis factor α (TNFα) in a mouse model of traumatic neuropathy using a small cell permeable molecule (R7050) that inhibits TNFα/TNF receptor 1 (TNFR1) complex internalization. Adult pigmented mice were subjected to intraorbital optic nerve crush (ONC). Animals received daily intraperitoneal injections of R7050, and/or a single intravitreal administration the day of the surgery. Some animals received a combinatorial treatment with R7050 (systemic or local) and a single intravitreal injection of brain derived neurotrophic factor (BDNF). As controls, untreated animals were used. Retinas were analyzed for RGC survival 5 and 14 days after the lesion i.e., during the quick and slow phase of axotomy-induced RGC death. qPCR analyses were done to verify that Tnfr1 and TNFα were up-regulated after ONC. At 5 days post-lesion, R7050 intravitreal or systemic treatment neuroprotected RGCs as much as BDNF alone. At 14 days, RGC rescue by systemic or intravitreal administration of R7050 was similar. At this time point, intravitreal treatment with BDNF was significantly better than intravitreal R7050. Combinatory treatment was not better than BDNF alone, although at both time points, the mean number of surviving RGCs was higher. In conclusion, antagonism of the extrinsic pathway of apoptosis rescues axotomized RGCs as it does the activation of survival pathways by BDNF. However, manipulation of both pathways at the same time, does not improve RGC survival.

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Adalimumab improves cognitive impairment, exerts neuroprotective effects and attenuates neuroinflammation in an Aβ1-40-injected mouse model of Alzheimer's disease

Cited by 41 publications

References 68 publications

Neuroinflammation in Alzheimer’s Disease

Neuroinflammation in Alzheimer’s Disease

Repositioning of Immunomodulators: A Ray of Hope for Alzheimer’s Disease?

Systemic and Intravitreal Antagonism of the TNFR1 Signaling Pathway Delays Axotomy-Induced Retinal Ganglion Cell Loss

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