The Many Faces of Astrocytes in Alzheimer's Disease

Monterey, Michael; Wei, Haichao; Wu, Xizi; Wu, Jia Qian

doi:10.3389/fneur.2021.619626

Cited by 57 publications

(75 citation statements)

References 125 publications

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“…Developmental data show as well an intriguing spatiotemporal association between buildup of AβOs and GFAP-positive astrocytes. This link is intriguing given recent studies indicating an important role for astrocytes in memory loss (Huang et al, 2017;Monterey et al, 2021;Preeti et al, 2021) and in microglia pathology (Süß and Schlachetzki, 2020;Streit et al, 2021). Importantly, we demonstrate that antibodies targeting AβOs can be used as brain imaging probes to identify animals with AD pathology, indicating the potential of AβO-selective antibodies for diagnostics as well as therapeutics.…”

Section: Discussionmentioning

confidence: 54%

The Therapeutic and Diagnostic Potential of Amyloid β Oligomers Selective Antibodies to Treat Alzheimer’s Disease

et al. 2022

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Improvements have been made in the diagnosis of Alzheimer’s disease (AD), manifesting mostly in the development of in vivo imaging methods that allow for the detection of pathological changes in AD by magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. Many of these imaging methods, however, use agents that probe amyloid fibrils and plaques–species that do not correlate well with disease progression and are not present at the earliest stages of the disease. Amyloid β oligomers (AβOs), rather, are now widely accepted as the Aβ species most germane to AD onset and progression. Here we report evidence further supporting the role of AβOs as pathological instigators of AD and introduce promising anti-AβO diagnostic probes capable of distinguishing the 5xFAD mouse model from wild type mice by PET and MRI. In a developmental study, Aβ oligomers in 5xFAD mice were found to appear at 3 months of age, just prior to the onset of memory dysfunction, and spread as memory worsened. The increase of AβOs is prominent in the subiculum and correlates with concomitant development of reactive astrocytosis. The impact of these AβOs on memory is in harmony with findings that intraventricular injection of synthetic AβOs into wild type mice induced hippocampal dependent memory dysfunction within 24 h. Compelling support for the conclusion that endogenous AβOs cause memory loss was found in experiments showing that intranasal inoculation of AβO-selective antibodies into 5xFAD mice completely restored memory function, measured 30–40 days post-inoculation. These antibodies, which were modified to give MRI and PET imaging probes, were able to distinguish 5xFAD mice from wild type littermates. These results provide strong support for the role of AβOs in instigating memory loss and salient AD neuropathology, and they demonstrate that AβO selective antibodies have potential both for therapeutics and for diagnostics.

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Section: Discussionmentioning

confidence: 54%

The Therapeutic and Diagnostic Potential of Amyloid β Oligomers Selective Antibodies to Treat Alzheimer’s Disease

et al. 2022

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“…Multiple other enrichments are not discussed here but are shown in supplementary Table 11. Due to the importance of astrocytes in AD [22] and the enrichment in astrocytic genes we observed above we also looked at the AD GWAS genes for enrichments. Twenty-one AD-associated genes were present in the reference list of genes in our comparison, and 3 of them were among the 583 significantly higher in hiPSC-AN21 ( APOE, CLU and CASS4) , compared to 1.2 expected by chance.…”

Section: Resultsmentioning

confidence: 99%

“…We further compared them to the list of 207 genes reported as high confidence for ASD by SFARI. Of these 199 were present in our expressed gene list and 34 (17%) were significantly higher (12) or lower (22) in hiPSC-N21 (Suppl. Table 6), which is also significantly more (1.65-fold) than expected by chance (chi-squared p= 0.002).…”

Section: Differences Between Hipsc-n15 and Hipsc-n21mentioning

confidence: 99%

Insights for disease modeling from single cell transcriptomics of iPSC-derived Ngn2-induced neurons and astrocytes across differentiation time and co-culture

Das

Sonthalia

Stein-O’Brien

et al. 2022

Preprint

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Trans-differentiation of human induced pluripotent stem cells into neurons (hiPSC-N) via Ngn2-induction has become an efficient system to quickly generate neurons for disease modeling and in vitro assay development, a significant step up from previously used neoplastic and other cell lines. Recent single-cell interrogation of Ngn2-induced neurons however, has revealed some similarities to unexpected neuronal lineages. Similarly, a straightforward method to generate hiPSC derived astrocytes (hiPSC-A) for the study of neuropsychiatric disorders has also been described. Here we examine the homogeneity and similarity of hiPSC-N and hiPSC-A to their in vivo counterparts, the impact of different lengths of time post Ngn2 induction on hiPSC-N (15 or 21 days) and of hiPSC-N / hiPSC-A co-culture. We explore how often genes differentially expressed between conditions relate to genetic risk for neuropsychiatric disease. Leveraging the wealth of existing public single-cell RNA-seq (scRNA-seq) data in Ngn2-induced neurons and in vivo data from the developing brain, we provide perspectives on the lineage origins and maturation of hiPSC-N and hiPSC-A. Both show heterogeneity and share similarity with multiple in vivo cell fates, and both cell types more precisely approximate their in vivo counterparts when co-cultured. hiPSC-A show more heterogeneity and similarities to other non-neural cell types, especially when cultured in isolation. Gene expression data from the hiPSC-N show excess of genes linked to schizophrenia (SZ) and autism spectrum disorders (ASD) as has been previously shown for neural stem cells and neurons. These overrepresentations of disease genes are strongest in our system at early times (day 15) in Ngn2-induction/maturation of neurons, which together with our observation of similarities with in vivo neurons earlier in development suggest they may be a better model for neurodevelopmental disorders. We have assembled this new scRNA-seq data along with the public data explored here as an integrated biologist-friendly web-resource for researchers seeking to understand this system more deeply: https://nemoanalytics.org/p?l=DasEtAl2022.

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“…These findings are particularly intriguing given recent studies indicating AD's dependence on astrocytes (Huang et al, 2017;Monterey et al, 2021;Nisa et al, 2021;Preeti et al, 2021;Zhou et al, 2021). One especially interesting study showed that when apolipoprotein E (ApoE), a protein expressed in astrocytes which AβOs associate with at synapses, was knocked out in astrocyte-only populations of P301S mice, AD pathology markedly improved (Wang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

The therapeutic and diagnostic potential of amyloid β oligomers (AβOs) selective antibodies to treat Alzheimer’s disease

Viola

Bicca

Bebenek

et al. 2021

Preprint

View full text Add to dashboard Cite

Improvements have been made in the diagnosis of Alzheimer's disease (AD), manifesting mostly in the development of in vivo imaging methods that allow for the detection of pathological changes in AD by MRI and PET scans. Many of these imaging methods, however, use agents that probe amyloid fibrils and plaques- species that do not correlate well with disease progression and are not present at the earliest stages of the disease. Amyloid β oligomers (AβOs), rather, are now widely accepted as the Aβ species most germane to AD onset and progression. Here we report evidence further supporting the role of AβOs as pathological instigators of AD and introduce a promising anti-AβO diagnostic probe capable of distinguishing the 5xFAD mouse model from wild type mice by PET and MRI. In a developmental study, Aβ oligomers in 5xFAD mice were found to appear at 3 months of age, just prior to the onset of memory dysfunction, and spread as memory worsened. The increase is prominent in the subiculum and correlates with concomitant development of reactive astrocytosis. The impact of these AβOs on memory is in harmony with findings that intraventricular injection of synthetic AβOs into wild type mice induced hippocampal dependent memory dysfunction within 24 hours. Compelling support for the conclusion that endogenous AβOs cause memory loss was found in experiments showing that intranasal inoculation of AβO-selective antibodies into 5xFAD mice completely restored memory function, measured 30 days post-inoculation. These antibodies, which were modified to give MRI and PET imaging probes, were able to distinguish 5xFAD mice from wild type littermates. These results provide strong support for the role of AβOs in instigating memory loss and salient AD neuropathology, and they demonstrate that AβO selective antibodies have potential both for therapeutics and for diagnostics.

show abstract

The Many Faces of Astrocytes in Alzheimer's Disease

Cited by 57 publications

References 125 publications

The Therapeutic and Diagnostic Potential of Amyloid β Oligomers Selective Antibodies to Treat Alzheimer’s Disease

The Therapeutic and Diagnostic Potential of Amyloid β Oligomers Selective Antibodies to Treat Alzheimer’s Disease

Insights for disease modeling from single cell transcriptomics of iPSC-derived Ngn2-induced neurons and astrocytes across differentiation time and co-culture

The therapeutic and diagnostic potential of amyloid β oligomers (AβOs) selective antibodies to treat Alzheimer’s disease

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