Genomic deletion of TLR2 induces aggravated white matter damage and deteriorated neurobehavioral functions in mouse models of Alzheimer’s disease

Zhou, Chao; Sun, Xiaoyu; Hu, Yuting; Song, Jiaxing; Dong, Shuyu; Kong, Delian; Wang, Yuqiao; Hua, Xiaodong; Han, Jingjing; Zhou, Yan; Jia, Guanghong; Yang, Xinxin; Shi, Hang; Zhang, Zuohui; Fang, Hua

doi:10.18632/aging.102260

Cited by 34 publications

(35 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar results were obtained for TLR2 expression, except at the basal state of SMC subjects [ 165 , 166 ]. This is in line with data which found that the genomic deletion of TLR2 markedly deteriorated the neurobehavioral functions in a mouse model of AD [ 167 ]. This suggests that a functional balance should exist between the hyper- and hypoactivation of the TLRs [ 167 ].…”

Section: Discussionsupporting

confidence: 91%

“…This is in line with data which found that the genomic deletion of TLR2 markedly deteriorated the neurobehavioral functions in a mouse model of AD [ 167 ]. This suggests that a functional balance should exist between the hyper- and hypoactivation of the TLRs [ 167 ]. Conversely this decrease may also contribute further during infection to the deposition of Aβ by the decreased TLR2 expression [ 144 ].…”

Section: Discussionsupporting

confidence: 91%

See 1 more Smart Citation

Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease

Munawara

Catanzaro

et al. 2021

Immun Ageing

View full text Add to dashboard Cite

Background Alzheimer’s disease (AD) is the most common neurodegenerative disease ultimately manifesting as clinical dementia. Despite considerable effort and ample experimental data, the role of neuroinflammation related to systemic inflammation is still unsettled. While the implication of microglia is well recognized, the exact contribution of peripheral monocytes/macrophages is still largely unknown, especially concerning their role in the various stages of AD. Objectives AD develops over decades and its clinical manifestation is preceded by subjective memory complaints (SMC) and mild cognitive impairment (MCI); thus, the question arises how the peripheral innate immune response changes with the progression of the disease. Therefore, to further investigate the roles of monocytes/macrophages in the progression of AD we assessed their phenotypes and functions in patients at SMC, MCI and AD stages and compared them with cognitively healthy controls. We also conceptualised an idealised mathematical model to explain the functionality of monocytes/macrophages along the progression of the disease. Results We show that there are distinct phenotypic and functional changes in monocyte and macrophage populations as the disease progresses. Higher free radical production upon stimulation could already be observed for the monocytes of SMC patients. The most striking results show that activation of peripheral monocytes (hyperactivation) is the strongest in the MCI group, at the prodromal stage of the disease. Monocytes exhibit significantly increased chemotaxis, free radical production, and cytokine production in response to TLR2 and TLR4 stimulation. Conclusion Our data suggest that the peripheral innate immune system is activated during the progression from SMC through MCI to AD, with the highest levels of activation being in MCI subjects and the lowest in AD patients. Some of these parameters may be used as biomarkers, but more holistic immune studies are needed to find the best period of the disease for clinical intervention.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease

Munawara

Catanzaro

et al. 2021

Immun Ageing

View full text Add to dashboard Cite

show abstract

“…TLR2 binds to Aβ and mediates the Aβ phagocytosis by microglia [ 207 ]. Dysregulation of the TLR2 pathway accelerated memory impairment in AD mice, either through inhibition [ 208 , 209 , 210 ] or activation [ 207 ]. None of these agents have reached clinical trials for AD therapy.…”

Section: Novel Therapeutic Approachmentioning

confidence: 99%

Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review

Lane

Lin

2021

IJMS

104

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and accounts for most cases of dementia. The prevalence of AD has increased in the current rapidly aging society and contributes to a heavy burden on families and society. Despite the profound impact of AD, current treatments are unable to achieve satisfactory therapeutic effects or stop the progression of the disease. Finding novel treatments for AD has become urgent. In this paper, we reviewed novel therapeutic approaches in five categories: anti-amyloid therapy, anti-tau therapy, anti-neuroinflammatory therapy, neuroprotective agents including N-methyl-D-aspartate (NMDA) receptor modulators, and brain stimulation. The trend of therapeutic development is shifting from a single pathological target to a more complex mechanism, such as the neuroinflammatory and neurodegenerative processes. While drug repositioning may accelerate pharmacological development, non-pharmacological interventions, especially repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), also have the potential for clinical application. In the future, it is possible for physicians to choose appropriate interventions individually on the basis of precision medicine.

show abstract

“…The importance of TLR signaling in preventing the development of AD is highlighted by studies demonstrating how activation of TLR 2, 4, and 9 signaling can reduce brain pathology and plaque build-up (Tahara et al, 2006 ). Furthermore, TLR 4 and 2 knock-out mice demonstrate increased amyloid plaque burden and cognitive decline (Song et al, 2011 ; Zhou et al, 2019 ). The above affects appear to occur via reduced microglial phagocytosis of amyloid plaques.…”

Section: Pip Effects On Microglial Functions and Implications For Neurodegenerationmentioning

confidence: 99%

Phosphoinositides: Roles in the Development of Microglial-Mediated Neuroinflammation and Neurodegeneration

Phillips

Maguire

2021

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Microglia are increasingly recognized as vital players in the pathology of a variety of neurodegenerative conditions including Alzheimer’s (AD) and Parkinson’s (PD) disease. While microglia have a protective role in the brain, their dysfunction can lead to neuroinflammation and contributes to disease progression. Also, a growing body of literature highlights the seven phosphoinositides, or PIPs, as key players in the regulation of microglial-mediated neuroinflammation. These small signaling lipids are phosphorylated derivates of phosphatidylinositol, are enriched in the brain, and have well-established roles in both homeostasis and disease.Disrupted PIP levels and signaling has been detected in a variety of dementias. Moreover, many known AD disease modifiers identified via genetic studies are expressed in microglia and are involved in phospholipid metabolism. One of these, the enzyme PLCγ2 that hydrolyzes the PIP species PI(4,5)P2, displays altered expression in AD and PD and is currently being investigated as a potential therapeutic target.Perhaps unsurprisingly, neurodegenerative conditions exhibiting PIP dyshomeostasis also tend to show alterations in aspects of microglial function regulated by these lipids. In particular, phosphoinositides regulate the activities of proteins and enzymes required for endocytosis, toll-like receptor signaling, purinergic signaling, chemotaxis, and migration, all of which are affected in a variety of neurodegenerative conditions. These functions are crucial to allow microglia to adequately survey the brain and respond appropriately to invading pathogens and other abnormalities, including misfolded proteins. AD and PD therapies are being developed to target many of the above pathways, and although not yet investigated, simultaneous PIP manipulation might enhance the beneficial effects observed. Currently, only limited therapeutics are available for dementia, and although these show some benefits for symptom severity and progression, they are far from curative. Given the importance of microglia and PIPs in dementia development, this review summarizes current research and asks whether we can exploit this information to design more targeted, or perhaps combined, dementia therapeutics. More work is needed to fully characterize the pathways discussed in this review, but given the strength of the current literature, insights in this area could be invaluable for the future of neurodegenerative disease research.

show abstract

Genomic deletion of TLR2 induces aggravated white matter damage and deteriorated neurobehavioral functions in mouse models of Alzheimer’s disease

Cited by 34 publications

References 58 publications

Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease

Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease

Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review

Phosphoinositides: Roles in the Development of Microglial-Mediated Neuroinflammation and Neurodegeneration

Contact Info

Product

Resources

About