Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer’s disease mouse model with suppression of glymphatic clearance

Feng, Weixi; Wang, Ze; Hu, Xu; Wu, Ting; Marshall, Charles; Gao, Junying; Xiao, Ming

doi:10.21203/rs.2.19388/v2

Cited by 4 publications

(4 citation statements)

References 52 publications

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“…Based on this observation, it is likely that the OPTN E50K mutation may be connected to Aβ accumulation for both NTG and AD through its impairment of autophagy, which would otherwise remove Aβ peptides [52][53][54]. Another important pathologic process for both diseases is neuroin ammation triggered by astrocytes and microglia in response to protein aggregates and degenerated neurons [49,55]. Its occurrence was supported by our ndings where astrocytes and microglia were signi cantly activated in old OPTN E50K mice.…”

Section: Discussionsupporting

confidence: 65%

Proteomic Comparison of Aged and OPTN E50K Retina in the Development of Normal Tension Glaucoma

Liu

Wang

Shao

et al. 2021

Preprint

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Background: Progressive degeneration of retinal ganglion cells (RGCs) is a major characteristic of glaucoma, whose underlying mechanisms are still largely unknown. An E50K mutation in the Optineurin (OPTN) gene is a leading cause of normal tension glaucoma (NTG), directly affecting RGCs without high intraocular pressure and causing severe glaucomatous symptoms in clinical settings. A systematic analysis of the NTG mouse model is crucial for better understanding of the underlying pathological mechanisms for glaucoma.Methods: To elucidate proteomic and biochemical pathway alterations during NTG development, we established an OPTN E50K mutant mouse model through CRISPR/Cas9. Retinal proteins from resulting mice exhibiting glaucomatous phenotypes were subject to tandem mass tag-labelled quantitative proteomics. Retinal proteomes were analyzed through bioinformatics methods to characterize the molecular and functional signatures of NTG. Results: We identified 6364 quantitative proteins in our proteomic analysis. Bioinformatics analysis revealed that OPTN E50K mice experienced protein synthesis dysregulation, age-dependent energy defects and autophagy-lysosome pathway dysfunction. Certain biological features, including amyloid deposition, RNA splicing, microglia activation and reduction of crystallin production, were similar to Alzheimer’s Disease (AD). Conclusions: Our study is the first to describe proteomic and biochemical pathway alterations in NTG pathogenesis during disease advancement. Several proteomic signatures overlapped with retinal changes found in the AD mice model, suggesting the presence of common mechanisms between age-related degenerative disorders, as well as prospective new targets for diagnostic and therapeutic strategies.

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Section: Discussionsupporting

confidence: 65%

Proteomic Comparison of Aged and OPTN E50K Retina in the Development of Normal Tension Glaucoma

Liu

Wang

Shao

et al. 2021

Preprint

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“…Possibly, gadobutrol might be used as a surrogate marker of metabolic byproducts excreted via CSF. A significant amount of amyloid-β isoforms are indeed cleared via CSF; about ¼ of amyloid-β is cleared via CSF in rodents (50,51). Tau to some extent passes across the BBB, particularly in the presence of BBB disruption.…”

Section: Implications Of Observed Csf Elimination Time Course the Present Observations Indicate Thatmentioning

confidence: 99%

Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood

et al. 2021

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Background. Methodology for estimation of cerebrospinal fluid (CSF) tracer clearance could have wide clinical application in predicting excretion of intrathecal drugs and metabolic solutes from brain metabolism, and for diagnostic work-up of cerebrospinal fluid disturbances.Methods. The magnetic resonance imaging (MRI) contrast agent gadobutrol (Gadovist) was utilized as CSF tracer and injected into the lumbar CSF. Gadobutrol is contained outside blood vessels of the central nervous system (CNS) and is thus eliminated along extra-vascular pathways, analogous to many CNS metabolites and intrathecal drugs. Tracer enrichment was verified and assessed in CSF by MRI at level of the cisterna magna in parallel with obtaining blood samples through 48 hours.Results. In a reference patient cohort (REF; n=29), both enrichment within CSF and blood coincided in time. Blood concentration profiles of gadobutrol through 48 hours varied between patients diagnosed with CSF leakage (n=4), idiopathic normal pressure hydrocephalus dementia (iNPH; n=7), pineal cysts (n=8), and idiopathic intracranial hypertension (IIH; n=4). Conclusion.Assessment of CSF tracer clearance is clinically feasible and may provide a way to predict extra-vascular clearance of intrathecal drugs and endogenous metabolites from the CNS. The peak concentration in blood (at about 10 hrs) preceded by far peak tracer enhancement at MRI in extra-cranial lymphatic structures (at about 24 hrs) as shown in previous studies, indicating a major role of the spinal canal in CSF clearance capacity.

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“…Studies have shown the protective function of microglia activation at pre-symptomatic stages of amyloidosis both in animal models [12,15] and clinical studies [13,17]. Indeed, in patients in a preclinical stage of AD, microglia activation correlated with a slower cognitive decline [13] and amyloid deposition [14].…”

Section: -Discussionmentioning

confidence: 99%

“…However, whether microglia play a protective or detrimental role during AD progression remains controversial [7,11]. The beneficial role of microglia in containing plaque deposition and delaying cognitive impairment has been reported by several studies [12][13][14][15][16]. Nonetheless, chronic activation of microglia is a well-known cause of neuroinflammation and neurodegeneration [17][18][19].…”

Section: -Introductionmentioning

confidence: 99%

Association of microglia loss with hippocampal network impairments as a turning point in the amyloid pathology progression

Pizzirusso,

Preka,

Goikolea

et al. 2024

Preprint

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Alzheimer’s disease is a progressive neurological disorder causing memory loss and cognitive decline. The underlying causes of cognitive deterioration and neurodegeneration remain unclear, leading to a lack of effective strategies to prevent dementia. Recent evidence highlights the role of neuroinflammation, particularly involving microglia, in Alzheimer’s disease onset and progression. Characterizing the initial phase of Alzheimer’s disease can lead to the discovery of new biomarkers and therapeutic targets, facilitating timely interventions for effective treatments. We used theAppNL-G-Fknock-in mouse model, which resembles the amyloid pathology and neuroinflammatory characteristics of Alzheimer’s disease, to investigate the transition from a pre-plaque to an early plaque stage with a combined functional and molecular approach. Our experiments show a progressive decrease in the power of cognition-relevant hippocampal gamma oscillations during the early stage of amyloid pathology, together with a modification of fast-spiking interneuron intrinsic properties and postsynaptic input. Consistently, transcriptomic analyses revealed that these effects are accompanied by changes in synaptic function-associated pathways. Concurrently, homeostasis-and inflammatory-related microglia signature genes were downregulated. Moreover, we found a decrease in Iba1-positive microglia in the hippocampus that correlates with plaque aggregation and neuronal dysfunction. Collectively, these findings support the hypothesis that microglia play a protective role during the early stages of amyloid pathology by preventing plaque aggregation, supporting neuronal homeostasis, and overall preserving the oscillatory network’s functionality. These results suggest that the early loss of microglia could be a pivotal event in the progression of Alzheimer’s disease, potentially triggering plaque deposition, impairment of fast-spiking interneurons, and the breakdown of the oscillatory circuitry in the hippocampus.

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Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer’s disease mouse model with suppression of glymphatic clearance

Cited by 4 publications

References 52 publications

Proteomic Comparison of Aged and OPTN E50K Retina in the Development of Normal Tension Glaucoma

Proteomic Comparison of Aged and OPTN E50K Retina in the Development of Normal Tension Glaucoma

Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood

Association of microglia loss with hippocampal network impairments as a turning point in the amyloid pathology progression

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