Welcome to the AD/PD™ 2022 Interactive Program

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Displaying One Session

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE PLENARY: 115-117

NORMAL AND PATHOLOGICAL MICROGLIAL SIGNALLING PATHWAYS

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE PLENARY: 115-117
Lecture Time
09:10 AM - 09:25 AM

Abstract

Abstract Body

Genetic variants nearby, and in some cases, rare missense mutations in a variety of genes expressed in microglia associated with either increased or decreased risk for late onset Alzheimer’s disease (AD). These AD-associated genes include the triggering receptor expressed in myeloid cells 2 (TREM2), phospholipase C gamma 2 (PLCG2), Abl Interactor member 3 (ABI3), MS4A4 amongst others. We show here that Aβ oligomers, but not Aβ monomers, bind to TREM2 with nanomolar affinity, and induce Aβ-dose-dependent shedding of TREM2 ectodomain, DAP12 and SYK phosphorylation. Similar effects are induced by anti-TREM2 antibodies. We propose that these intracellular signalling pathway changes activate protective microglial mechanisms, and the AD related variants affect these mechanisms. In addition, we show that the shed soluble sTREM also has protective effects, inhibiting Aβ oligomer formation, disrupting preformed Aβ oligomers and reducing Aβ-induced neurotoxicity. Crucially, R47H sTREM2 failed to disrupt Aβ oligomerization, and in fact encouraged larger more neurotoxic oligomers. sTREM2 and TREM2 signalling pathways represent potential therapeutic targets.

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CELLULAR INTERACTIONS OF MICROGLIA IN NEURODEGENERATIVE DISEASE

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE PLENARY: 115-117
Lecture Time
09:25 AM - 09:40 AM

Abstract

Abstract Body

The intraneuronal or extracellular accumulation of neurotoxic beta-sheet structured amyloids represent key pathological hallmarks of several neurodegenerative disease. While the brain has been considered an immune-privileged organ, increasing evidence suggests that innate immune cells are intimately involved in disease evolution and progression.

Microglia play a pivotal role for this innate immune response and are activated by binding of protein aggregates to pattern recognition receptors. This binding may activate pathways that are involved in phagocytosis and degradation. On the other hand, immune activation of microglia may lead to the release of inflammatory mediators and distracts microglia from their physiological functions and tasks. Microglial distribution of neurotoxic beta-sheet structured cargo may help stressed cells to cope with the inflammatory activation and contribute to the overall successful clearance. Importantly, disease causing mutations and risk polymorphisms for neurodegenerative disease such as Parkinson’s disease and Alzheimer’s disease are being tested for the potential to influence cargo distribution through tunneling nanotubes. Likewise, immune cells help each other by sharing intact mitochondria in order to cover the increased energy demand during an inflammatory challenge. The capability of microglia providing such help to neighboring cells may be key to prevent neurodegeneration.

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INTERACTION BETWEEN NEURONES AND GLIAL CELLS IN NEURODEGENERATIVE DISEASES WITH PROTEIN AGGREGATION

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE PLENARY: 115-117
Lecture Time
09:40 AM - 09:55 AM

ASTROCYTES ARE INVOLVED IN NETWORK HYPERACTIVITY AT EARLY STAGES OF AMYLOID PATHOLOGY

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE PLENARY: 115-117
Lecture Time
09:55 AM - 10:10 AM

Abstract

Aims

Hyperactivity of neurons and brain networks is one of the earliest functional changes observed in several mouse models of amyloid pathology (1). Aberrant network activity is a consequence of increased excitatory neurotransmission caused by deposition of abnormal amyloid protein. We hypothesize that dysfunction of astrocytes could contribute to network abnormalities, given their role in maintaining excitatory/inhibitory balance

Methods

All experiments were performed in the cingulate cortex, a default-mode-network node which is consistently affected in AD patients. We performed in-vivo two-photon calcium imaging of astrocytes in 3 months old APP NLF knock-in mice (2), before amyloid deposition. We then used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to modulate astrocyte calcium signals and performed calcium imaging, behavior analyses and resting-state functional MRI to assess the effects on neuronal activity, behavior hyperactivity and brain connectivity.

Results

We demonstrate a deficit of astrocyte calcium signaling in NLF mice, at the same time that they show increased neuronal activity. DREADDs enabled recovery of astrocyte calcium signals to control levels. Furthermore, rescuing astrocyte calcium signals normalized neuronal hyper-excitability, a key defect in early AD. In addition, recovery of astrocyte function also decreased behavioral hyperactivity and seizure susceptibility.

Conclusions

These results point to a possible causal relation between astrocytes and brain hyperactivity in early AD. Moreover, recovering astrocyte function also decreased hyper-connectivity between the cingulate-retrosplenial cortex, which we observed with rsfMRI, opening doors to translation to AD patients.

1)Busche MA, Konnerth A. Philos Trans R Soc B Biol Sci. 2016;371(1700):20150429.

2) Saito T et al., Nat Neurosci. 2014;17(5):661-663.

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EXPLORING THE TRANSCRIPTOMIC DIVERSITY OF LIVE HUMAN MICROGLIA IN AGING, NEURODEGENERATION, AND NEUROINFLAMMATION

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE PLENARY: 115-117
Lecture Time
10:10 AM - 10:25 AM

Abstract

Aims

We hypothesized that single-cell sequencing of human microglia from diverse neurological diseases and central nervous system (CNS) regions would reveal microglial subtypes and functional states with distinct disease relevance.

Methods

Using the 10x Chromium platform and our pipeline for extracting live human microglia, we profiled microglia from an array of neurological diseases including Alzheimer’s and Parkinson’s. We sampled diverse CNS regions including neocortex, substantia nigra, and hippocampus. To confirm our findings, we optimized a dual-detection immunofluorescence and RNAscope pipeline followed by automated segmentation to capture microglial transcripts and morphology.

Results

After rigorous pre-processing, we retained 215,658 live, human microglial transcriptomes. We identified 12 microglial subsets with an intriguing central split between oxidative and heterocyclic metabolism in the differentiation tree. Distinct subsets appear to be specialized for antigen-presentation, motility, and proliferation. Using our dual-detection pipeline, we validated the presence of our subsets in human tissue. We demonstrate enrichment of gene sets associated with Alzheimer’s disease in one microglial subset, but no microglial subset is enriched for Parkinson’s disease genes. We illustrate the use of our reference by analyzing data from a chimeric model where human iPSC-derived microglia are introduced into the mouse brain. Using a pairwise machine learning approach, we note that transplanted microglia-like cells align mostly with our homeostatic-active subset, with a few mapping to disease-enriched, antigen-presentation, or proliferation-associated clusters.

Conclusions

Our work provides a new reference for understanding human microglial heterogeneity and tools for studying microglial heterogeneity in situ. Further work remains to be done on exploring the functional roles of distinct microglial subsets.

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IDENTIFICATION, CHARACTERIZATION, AND THERAPEUTIC TARGETING OF NOVEL MICROGLIAL PATHWAYS UNDERLYING ALZHEIMER’S DISEASE

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE PLENARY: 115-117
Lecture Time
10:25 AM - 10:40 AM

Abstract

Abstract Body

Objectives: Alzheimer’s disease (AD) is noted for a robust microglial response. Recent genetic studies have identified several genetic risk variants that are predominantly expressed in microglia and associated with innate immunity. Among these risk genes is phospholipase C gamma 2 (PLCG2), a key regulatory hub for immune signaling. The hypermorphic P522R variant of PLCG2 has been reported to confer protection against AD. We have identified the less active M28L variant as a novel PLCG2 variant associated with elevated AD risk. Our aims were to examine the role of PLCG2 in AD and investigate mechanisms discriminating divergent effects of PLCG2 variants on AD risk.

Methods: RNA-Seq data from human brains was queried to determine the role of PLCG2 in AD. To ascertain if PLCG2 risk variants alter microglial responses to amyloid plaques, we generated mice bearing the M28L risk or the P522R protective PLCG2 variant, all
crossed onto the 5xFAD murine model of AD.

Methods: RNA-Seq data from human brains was queried to determine the role of PLCG2 in AD. To ascertain if PLCG2 risk variants alter microglial responses to amyloid plaques, we generated mice bearing the M28L risk or the P522R protective PLCG2 variant, all
crossed onto the 5xFAD murine model of AD.

Results: PLCG2 expression was upregulated in AD brains and correlated with amyloid plaque density. PLCG2 gene expression was associated with pathways related to inflammatory response. Similar results were observed in 5xFAD mice. Primary murine microglia with the M28L variant of PLCG2 showed reduced uptake capacity of amyloid. PLCG2 variants affected plaque pathology, altered microglial phenotypes, and drove distinct transcriptional phenotypes of microglia in the presence of amyloid pathology in 5xFAD mice.

Conclusions: PLCG2 variants confer divergent microglial phenotypic function in AD pathophysiology and defining these differences will be important in the development of microglia-directed therapeutics.
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PRE-RECORDED: TRANSLATIONAL IMAGING STUDIES OF REACTIVE ASTROCYTES AT DIFFERENT STAGES OF AD- IMPLICATION FOR EARLY DIAGNOSIS AND TREATMENT

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE PLENARY: 115-117
Lecture Time
10:40 AM - 10:55 AM

Abstract

Abstract Body

Astrocytes in brain play an important role in maintaining an optimal brain function including direct regulation of synapse activity and via cross talks between glia and neurons. The respond of astrocytes to changes in brain homoeostasis are observed by defence processes named reactive astrogliosis. An increased astrogliosis is detected by PET imaging in early stages of AD as well in other non-AD dementia such as frontotemporal dementia. Reactive astrocytes seem to be closely related to both amyloid and tau in brain but also to cerebral metabolisms and microstructures, . PET data suggest that high levels of reactive astrogliosis in early presymptomatic stages of AD may precede some other pathological hallmarks of AD. Ongoing PET studies in autosomal dominant and sporadic AD individuals aim to investigate whether astrogliosis are driving the propagation of tau during disease progression with cognitive decline. Our translational in vivo / in vitro tracer imaging studies suggest the presence of ” a first and a second wave” of reactive astrogliosis in AD and with different relationship with other AD pathology biomarkers at the different stages of the disease. New promising PET tracers for visualizing reactive astrogliosis in brain provide further valuable insight to disease mechanisms for both AD and other non-AD dementia. The clinical value of new fluid astrocytes biomarkers and their relationship to brain astrogliosis as well as to other fluid and brain biomarkers represent new avenues which presently are under exploration and also might be provide new tools for evaluation of new drug targets.

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PRE-RECORDED: ALZHEIMER’S DISEASE IS A GENETICALLY HETEROGENEOUS INNATE IMMUNE DISORDER

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE PLENARY: 115-117
Lecture Time
10:55 AM - 11:10 AM

Abstract

Abstract Body

Among the growing number of genes associated with risk for Alzheimer’s disease (AD), the fastest growing group are involved with innate immunity. We reported the first AD-associated innate immune AD gene, CD33, in 2008, which was followed by the report of association of AD with TREM2. Using knockouts of these genes in 5XFAD mice, we have demonstrated these two genes to confer opposite effects on microglial activation. While knockout of CD33 led to increased microglial clearance of Aβ and improved cognitive performance, TREM2 knockout had opposite effects in 5XFAD mice. Another innate immune AD-associated gene, INPP5D, encodes SHIP1, an adaptor for TYROBP (DAP12) in the TREM2 transduction pathway. In preliminary studies, knockdown of INPP5D in BV2 murine microglia led to increased phagocytosis of Aβ, increased autophagy, and increased lysosomal compartment size. In an extension of the role of innate immunogenetics in AD, we have reported that Aβ is an antimicrobial peptide that can protect against microbes such as viruses, bacteria, and fungus. Binding of Aβ to microbes rapidly nucleates amyloid depositon, which entraps the microbe, affording host cell defense. Preliminary studies indicate that both viral infection and Aβ deposition trigger neurofibrillary tangles, which physically block neurotropic spread of viruses. In view of these findings, we propose that AD neuropathology is an evolutionarily-conserved, orchestrated set of innate immune responses that evolved to protect the brain against infection. We further posit that AD-associated genetic risk variants evolved during epidemics of encephalitis and meningitis, owing to their ability to afford protection against brain infection.

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