Programmed Cell Death Protein 1 Blockade Reduces Glycogen Synthase Kinase 3β Activity and Tau Hyperphosphorylation in Alzheimer’s Disease Mouse Models

Zou, Yi; Gan, Chen‐Ling; Xin, Zhiming; Zhang, Haitao; Zhang, Qi; Lee, Tae Ho; Pan, Xiaodong; Zhou, C.

doi:10.3389/fcell.2021.769229

Cited by 10 publications

(6 citation statements)

References 49 publications

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“…Using an in vivo study with PD-1 KO mice as a control and immunohistochemical detection, they also found that after Aβ42 insult, the expression of PD-1 and PD-L1 increased. 31 Similar conclusions were drawn from a study by Wu et al in 2022, finding that AD patients exhibit higher levels of PD-L1/2 expression but no difference in PD-1 expression. They utilized flow cytometry on PBMCs extracted from sixteen AD patients.…”

Section: Pd-1/pd-l1 Blockade and Adsupporting

confidence: 81%

PD-1/PD-L1 Inhibitors for Alzheimer’s Pathology: A Literature Review

Huang,

Long,

Lau

et al. 2024

Preprint

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Alzheimer’s Disease (AD) is a neurodegenerative disease where the buildup of insoluble amyloid-beta plaques causes synaptic dysfunction, tau pathology, and loss of neurons, which leads to mood disorders, mental decline, and dementia. PD-1/PD-L1 is an immune checkpoint which involves the binding of PD-L1 (Programmed Death Ligand 1) on a target cell to the PD-1 receptor (Programmed Cell Death Protein 1) on an immune cell. This immune checkpoint allows for the suppression and regulation of the immune system. Previous studies have shown that the blockade of PD-1/PD-L1 allows for the activation of the immune cell and pro-inflammatory responses. However, in AD, chronic neuroinflammation has been strongly linked with the pathogenesis of the disease. The use of PD-1 inhibitors in AD is unorthodox, but not unfounded, since the blockade of PD-1/PD-L1 can reduce local brain inflammation by the recruitment of immune cells for Aβ clearance, even if the immune cells are pro-inflammatory. Furthermore, PD-1 inhibitors have been found to inhibit tauopathy and there is even potential in efficient combination therapies with NOD2. The PD-1/PD-L1 axis in neuroinflammation and AD is highly complex, and through this review, we aim to provide some insight into this relationship and explore the potential of it as an AD treatment.

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Section: Pd-1/pd-l1 Blockade and Adsupporting

confidence: 81%

PD-1/PD-L1 Inhibitors for Alzheimer’s Pathology: A Literature Review

Huang,

Long,

Lau

et al. 2024

Preprint

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“…In the future, developing new senolytic therapies that exclusively target senescent cells, or specifically, senescent microglia should be considered. In line with these contentions are the findings of the beneficial effect of targeting the inhibitory immune checkpoint pathway, PD-1/PD-L1 in animal models of AD and tauopathy, through a mechanism that involves reduced inflammation [43][44][45][46] and anti-aging effect through a mechanism that reduces the abundance of senescent cells in all tissues tested 47,48 .…”

Section: Discussionmentioning

confidence: 78%

TREM2-dependent senescent microglia conserved in aging and Alzheimer’s disease

Rachmian

Medina

Cherqui

et al. 2023

Preprint

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Dementia in general, and Alzheimer's disease (AD) in particular, are age-related diseases (1,2). AD is associated with multiple causative factors (3,4), among which local brain inflammation plays a significant role (5). Microglia, the brain-resident immune cells, are activated along the disease course (6,7). Yet, their contribution to the disease progression is still controversial. Here, using high-throughput mass cytometry for microglial immuno-phenotyping, we identified accumulation of senescent microglia in several pathologies associated with cognitive decline. These senescent microglia have a unique profile conserved across the multiple conditions investigated, including aging, mouse models of amyloidosis, and tauopathy. Moreover, we found that the expression of markers of senescence correlates with levels of TREM2, whose polymorphism was identified by GWAS as an AD risk factor (8,9). A TREM2-null AD mouse model showed lower levels of senescent microglia, relative to TREM2-intact AD mice. Senolysis using the drug ABT-73710,11 in an AD mouse model reduced the abundance of TREM2-senescent microglia without affecting levels of TREM2-dependent activated microglia, ameliorated cognitive deficits, and reduced brain inflammation. These results reveal the unexpected contribution of TREM2 to accumulation of senescent microglia in AD pathology, an effect that must be considered when targeting TREM2 as a therapeutic approach.

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“… 170 Recent studies unearthed a PDL1‐GSK3β immune complex within the brains of APP/PS1 and 5×FAD mice, an entity that heightens GSK3β activity and p‐tau levels. 171 …”

Section: The Role Of Gsk3 In Admentioning

confidence: 99%

“…170 Recent studies unearthed a PDL1-GSK3β immune complex within the brains of APP/PS1 and 5×FAD mice, an entity that heightens GSK3β activity and p-tau levels. 171 The preceding paragraph has indicated the potential of ILK to augment the inhibitory effects on GSK3. 7 In N1E-115 neuroblastoma cells, inactivation of ILK led to the loss of its inhibitory effect on GSK3β, which subsequently caused an elevation in p-tau levels.…”

Section: Gsk3 Signaling Mediated By Other Proteins In Tau Pathologymentioning

confidence: 99%

GSK3: A potential target and pending issues for treatment of Alzheimer's disease

Zhao,

Wei,

Guo

et al. 2024

CNS Neurosci Ther

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Glycogen synthase kinase‐3 (GSK3), consisting of GSK3α and GSK3β subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed increased GSK3 expression in the brains of Alzheimer's disease (AD) patients and models. AD is a neurodegenerative disorder with diverse pathogenesis and notable cognitive impairments, characterized by Aβ aggregation and excessive tau phosphorylation. This article provides an overview of GSK3's structure and regulation, extensively analyzing its relationship with AD factors. GSK3 overactivation disrupts neural growth, development, and function. It directly promotes tau phosphorylation, regulates amyloid precursor protein (APP) cleavage, leading to Aβ formation, and directly or indirectly triggers neuroinflammation and oxidative damage. We also summarize preclinical research highlighting the inhibition of GSK3 activity as a primary therapeutic approach for AD. Finally, pending issues like the lack of highly specific and affinity‐driven GSK3 inhibitors, are raised and expected to be addressed in future research. In conclusion, GSK3 represents a target in AD treatment, filled with hope, challenges, opportunities, and obstacles.

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Programmed Cell Death Protein 1 Blockade Reduces Glycogen Synthase Kinase 3β Activity and Tau Hyperphosphorylation in Alzheimer’s Disease Mouse Models

Cited by 10 publications

References 49 publications

PD-1/PD-L1 Inhibitors for Alzheimer’s Pathology: A Literature Review

PD-1/PD-L1 Inhibitors for Alzheimer’s Pathology: A Literature Review

TREM2-dependent senescent microglia conserved in aging and Alzheimer’s disease

GSK3: A potential target and pending issues for treatment of Alzheimer's disease

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