Pathological tau and reactive astrogliosis are associated with distinct functional deficits in a mouse model of tauopathy

Patel, Henika; Martínez, Paula; Perkins, Abigail; Taylor, Xavier; Jury, Nur; McKinzie, David L.; Lasagna‐Reeves, Cristian A.

doi:10.1016/j.neurobiolaging.2021.09.006

Cited by 25 publications

(34 citation statements)

References 68 publications

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“…Locomotor hyperactivity was attenuated by chronic etanercept treatment but not TfRMAb-TNFR treatment, paralleling the reduction in AT8-positive tau lesions with these TNF-α inhibitors in the male mice. Though the PS19 mice display a hyperactive phenotype, these mice may also display deficits in hippocampal-dependent learning [ 39 – 41 ], and future work will investigate the effects of the biologic TNF-α inhibitors using different hippocampal-dependent memory testing paradigms.…”

Section: Discussionmentioning

confidence: 99%

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Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy

Yang

Simanauskaite

et al. 2021

J Neuroinflammation

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Background Tumor necrosis factor-α (TNF-α) plays a central role in Alzheimer’s disease (AD) pathology, making biologic TNF-α inhibitors (TNFIs), including etanercept, viable therapeutics for AD. The protective effects of biologic TNFIs on AD hallmark pathology (Aβ deposition and tau pathology) have been demonstrated. However, the effects of biologic TNFIs on Aβ-independent tau pathology have not been reported. Existing biologic TNFIs do not cross the blood–brain barrier (BBB), therefore we engineered a BBB-penetrating biologic TNFI by fusing the extracellular domain of the type-II human TNF-α receptor (TNFR) to a transferrin receptor antibody (TfRMAb) that ferries the TNFR into the brain via receptor-mediated transcytosis. The present study aimed to investigate the effects of TfRMAb-TNFR (BBB-penetrating TNFI) and etanercept (non-BBB-penetrating TNFI) in the PS19 transgenic mouse model of tauopathy. Methods Six-month-old male and female PS19 mice were injected intraperitoneally with saline (n = 12), TfRMAb-TNFR (1.75 mg/kg, n = 10) or etanercept (0.875 mg/kg, equimolar dose of TNFR, n = 10) 3 days/week for 8 weeks. Age-matched littermate wild-type mice served as additional controls. Blood was collected at baseline and 8 weeks for a complete blood count. Locomotion hyperactivity was assessed by the open-field paradigm. Brains were examined for phosphorylated tau lesions (Ser202, Thr205), microgliosis, and neuronal health. The plasma pharmacokinetics were evaluated following a single intraperitoneal injection of 0.875 mg/kg etanercept or 1.75 mg/kg TfRMAb-TNFR or 1.75 mg/kg chronic TfRMAb-TNFR dosing for 4 weeks. Results Etanercept significantly reduced phosphorylated tau and microgliosis in the PS19 mouse brains of both sexes, while TfRMAb-TNFR significantly reduced these parameters in the female PS19 mice. Both TfRMAb-TNFR and etanercept treatment improved neuronal health by significantly increasing PSD95 expression and attenuating hippocampal neuron loss in the PS19 mice. The locomotion hyperactivity in the male PS19 mice was suppressed by chronic etanercept treatment. Equimolar dosing resulted in eightfold lower plasma exposure of the TfRMAb-TNFR compared with etanercept. The hematological profiles remained largely stable following chronic biologic TNFI dosing except for a significant increase in platelets with etanercept. Conclusion Both TfRMAb-TNFR (BBB-penetrating) and non-BBB-penetrating (etanercept) biologic TNFIs showed therapeutic effects in the PS19 mouse model of tauopathy.

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Section: Discussionmentioning

confidence: 99%

“…Since the PS19 mice consistently demonstrate a hyperactivity phenotype compared to cognitive deficits [ 39 – 41 ], we used the open-field test to measure locomotion hyperactivity. The open-field test was performed after 8 weeks of treatment (during week 9) as described previously [ 42 – 44 ].…”

Section: Methodsmentioning

confidence: 99%

Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy

Yang

Simanauskaite

et al. 2021

J Neuroinflammation

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“…No statistical methods were used to predetermine sample sizes, but our sample sizes are similar to those reported in previous publications 23,39,66,67 . All statistical analysis and graph designs were performed using GraphPad Prism 9.…”

Section: Statistics and Reproducibilitymentioning

confidence: 65%

Bassoon contributes to tau-seed propagation and neurotoxicity

et al. 2022

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Tau aggregation is a defining histopathological feature of Alzheimer’s disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer’s disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies.

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“…to acquire neuroprotective and deleterious signatures in response to tau in PS19 mice and Aβ pathology in APP/PS1 mice [86]. Tau induced reactive astrocytes and loss of their neurosupportive functions in mouse models, including PS19, Thy-Tau22, hTau and rTgTauEC mice [52,[103][104][105][106][107][108]. Astrogliosis in turn could increase tau hyperphosphorylation and aggregation [109].…”

Section: Discussionmentioning

confidence: 99%

Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-beta

Kecheliev

Boss

Maheshwari

et al. 2022

Preprint

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Neurovascular-glymphatic dysfunction plays an important role in Alzheimer’s disease and has been analyzed mainly in association with amyloid-beta (Aβ) pathology. The neurovascular-glymphatic link with tauopathies has not been well elucidated. Here, we aimed to investigate the alterations in the neurovasculature and map the aquaporin 4 (AQP4) distribution and depolarization associated with tau and Aβ. Perfusion, susceptibility weighted imaging and structural magnetic resonance imaging (MRI) were performed in the pR5 P301L mouse model of 4-repeat tau and the arcAβ mouse model of amyloidosis. Immunofluorescence staining was performed using antibodies against AQP4, CD31, astroglia (GFAP, s100β), phospho-tau (AT-8) and Aβ (6E10) in brain tissue slices from P301L, arcAβ and nontransgenic mice. P301L mice showed regional atrophy, preserved cerebral blood flow and reduced cerebral vessel density compared to nontransgenic mice, while arcAβ mice showed cerebral microbleeds and reduced cerebral vessel density. AQP4 depolarization and peri-tau enrichment in the hippocampus and increased AQP4 levels in the forebrain and hippocampus were detected in P301L mice compared to nontransgenic mice. In comparison, cortical AQP4 depolarization and cortical/hippocampal peri-plaque increases were observed in arcAβ mice. Increased s100β-GFAP fluorescence intensities indicative of reactive astrocytes were detected surrounding tau inclusions in P301L mice and Aβ plaques in arcAβ mice. In conclusion, we observed a divergent region-specific AQP4 increase and association with phospho-tau and Aβ pathologies.

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Pathological tau and reactive astrogliosis are associated with distinct functional deficits in a mouse model of tauopathy

Cited by 25 publications

References 68 publications

Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy

Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy

Bassoon contributes to tau-seed propagation and neurotoxicity

Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-beta

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