Astrocyte senescence in an Alzheimer’s disease mouse model is mediated by TGF-β1 and results in neurotoxicity

Amram, Shoshik; Iram, Tal; Lazdon, Ekaterina; Vassar, Robert; Ben-Porath, Ittai; Frenkel, Dan

doi:10.1101/700013

Cited by 4 publications

(4 citation statements)

References 45 publications

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“…Additionally, IL-6 is the most prominent component of the senescence-associated secretory phenotype released by senescent cells (Coppe, Desprez, Krtolica, & Campisi, 2010;Ghosh & Capell, 2016), whose contribution to age-related neurodegeneration, such as AD and PD, has recently been attributed to glial senescence (Bussian et al, 2018;Chinta et al, 2018;Zhang et al, 2019). In 5XFAD mice, the senescence state of astrocytes and their compromised Aβ clearance was recently described (Amram et al, 2019;Iram et al, 2016). In addition, the hyperactive mTOR pathway was shown to cause aging and senescence in various cell types, tissues, and organisms (Weichhart, 2018), and it has also been suggested that it represents a molecular pathway that is associated with the development of AD (Caccamo, De Pinto, Messina, Branca, & Oddo, 2014).…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C eta is activated in reactive astrocytes of an Alzheimer's disease mouse model: Evidence for its immunoregulatory function in primary astrocytes

Muraleedharan

Rotem-Dai

Strominger

et al. 2020

Glia

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Alzheimer's disease (AD) is the primary cause of age‐related dementia. Pathologically, AD is characterized by synaptic loss, the accumulation of β‐amyloid peptides and neurofibrillary tangles, glial activation, and neuroinflammation. Whereas extensive studies focused on neurons and activation of microglia in AD, the role of astrocytes has not been well‐characterized. Protein kinase C (PKC) was also implicated in AD; however, its role in astrocyte activation was not elucidated. Using the 5XFAD mouse model of AD, we show that PKC‐eta (PKCη), an astrocyte‐specific stress‐activated and anti‐apoptotic kinase, plays a role in reactive astrocytes. We demonstrate that PKCη staining is highly enriched in cortical astrocytes in a disease‐dependent manner and in the vicinity of amyloid‐β peptides plaques. Moreover, activation of PKCη, as indicated by its increased phosphorylation levels, is exhibited mainly in cortical astrocytes derived from adult 5XFAD mice. PKCη activation was associated with elevated levels of reactive astrocytic markers and upregulation of the pro‐inflammatory cytokine interleukin 6 (IL‐6) compared to littermate controls. Notably, inhibiting the kinase activity of PKCη in 5XFAD astrocyte cultures markedly increased the levels of secreted IL‐6—a phenomenon that was also observed in wild‐type astrocytes stimulated by inflammatory cytokines (e.g., TNFα, IL‐1). Similar increase in the release of IL‐6 was also observed upon inhibition of either the mammalian target of rapamycin (mTOR) or the protein phosphatase 2A (PP2A). Our findings suggest that the mTOR‐PKCη‐PP2A signaling cascade functions as a negative feedback loop of NF‐κB‐induced IL‐6 release in astrocytes. Thus, we identify PKCη as a regulator of neuroinflammation in AD.

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Section: Discussionmentioning

confidence: 99%

Protein kinase C eta is activated in reactive astrocytes of an Alzheimer's disease mouse model: Evidence for its immunoregulatory function in primary astrocytes

Muraleedharan

Rotem-Dai

Strominger

et al. 2020

Glia

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“…Furthermore, the pharmacological attenuation of age-associated TGFβ activation has rejuvenating effects in the aged brain [ 73 , 180 ], including the suppression of cellular senescence [ 181 ]. In astrocytes, previous reports have identified triggers of astrocyte senescence, such as oxidative stress [ 146 ], Aβ oligomers [ 148 , 182 ], HIV infection, and drug abuse [ 147 ]. Notably, TGFβ signaling is also implicated in these senescence mechanisms.…”

Section: Perspectives On Bbbd Tgfβ Signaling and Astrocyte Senescence...mentioning

confidence: 99%

Blood–Brain Barrier Dysfunction and Astrocyte Senescence as Reciprocal Drivers of Neuropathology in Aging

Preininger

Kaufer

2022

IJMS

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As the most abundant cell types in the brain, astrocytes form a tissue-wide signaling network that is responsible for maintaining brain homeostasis and regulating various brain activities. Here, we review some of the essential functions that astrocytes perform in supporting neurons, modulating the immune response, and regulating and maintaining the blood–brain barrier (BBB). Given their importance in brain health, it follows that astrocyte dysfunction has detrimental effects. Indeed, dysfunctional astrocytes are implicated in age-related neuropathology and participate in the onset and progression of neurodegenerative diseases. Here, we review two mechanisms by which astrocytes mediate neuropathology in the aging brain. First, age-associated blood–brain barrier dysfunction (BBBD) causes the hyperactivation of TGFβ signaling in astrocytes, which elicits a pro-inflammatory and epileptogenic phenotype. Over time, BBBD-associated astrocyte dysfunction results in hippocampal and cortical neural hyperexcitability and cognitive deficits. Second, senescent astrocytes accumulate in the brain with age and exhibit a decreased functional capacity and the secretion of senescent-associated secretory phenotype (SASP) factors, which contribute to neuroinflammation and neurotoxicity. Both BBBD and senescence progressively increase during aging and are associated with increased risk of neurodegenerative disease, but the relationship between the two has not yet been established. Thus, we discuss the potential relationship between BBBD, TGFβ hyperactivation, and senescence with respect to astrocytes in the context of aging and disease and identify future areas of investigation in the field.

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“…Therefore, developing drug delivery strategies across the blood-brain barrier (BBB) is important for therapeutic purposes. [5][6][7][8][9] Lactoferrin (Lf) is a human cationic iron (Fe) that binds with glycoprotein belonging to the transferrin (Tf) group. It has numerous biological functions such as intense antimicrobial, immunomodulatory, and anti-inflammatory functions.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, developing drug delivery strategies across the blood–brain barrier (BBB) is important for therapeutic purposes. 5 - 9 …”

Section: Introductionmentioning

confidence: 99%

Lactoferrin-Loaded PEG/PLA Block Copolymer Targeted With Anti-Transferrin Receptor Antibodies for Alzheimer Disease

Xiang-hong

Wan

et al. 2020

Dose-Response

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Last few years, struggles have been reported to develop the nanovesicles for drug delivery via the brain–blood barrier (BBB). Novel drugs, for instance, iAβ5, are efficient to inhibit the aggregates connected to the treatment of Alzheimer disease and are being evaluated, but most of the reports reflect some drawbacks of the drugs to reach the brain in preferred concentrations owing to the less BBB penetrability of the surface dimensions. In this report, we designed and developed a new approach to enhance the transport of drug via BBB, constructed with lactoferrin (Lf)-coated polyethylene glycol-polylactide nanoparticles (Lf-PPN) with superficial monoclonal antibody-functionalized antitransferrin receptor and anti-Aβ to deliver the iAβ5 hooked on the brain. The porcine brain capillary endothelial cells were utilized as BBB typically to examine the framework efficacy and toxicity. The cellular uptake of the immuno-nanoparticles with measured conveyance of the iAβ5 peptide was significantly enhanced and associated with Lf-PPN without monoclonal antibody functionalizations.

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Astrocyte senescence in an Alzheimer’s disease mouse model is mediated by TGF-β1 and results in neurotoxicity

Cited by 4 publications

References 45 publications

Protein kinase C eta is activated in reactive astrocytes of an Alzheimer's disease mouse model: Evidence for its immunoregulatory function in primary astrocytes

Protein kinase C eta is activated in reactive astrocytes of an Alzheimer's disease mouse model: Evidence for its immunoregulatory function in primary astrocytes

Blood–Brain Barrier Dysfunction and Astrocyte Senescence as Reciprocal Drivers of Neuropathology in Aging

Lactoferrin-Loaded PEG/PLA Block Copolymer Targeted With Anti-Transferrin Receptor Antibodies for Alzheimer Disease

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