Welcome to the AD/PD™ 2022 Interactive Program

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Displaying One Session

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 112

SPATIAL TRANSCRIPTOMICS TO ANALYZE THE PATHOLOGICAL CELLULAR NICHES IN ALZHEIMER’S DISEASE

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 112
Lecture Time
04:15 PM - 04:30 PM

UNCOVERED PATHOLOGICAL FUNCTION OF PLAQUE ASSOCIATED MICROGLIA WITH HIGHLY TRANSMISSIBLE SECRETORY PROPERTY

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 112
Lecture Time
04:30 PM - 04:45 PM

Abstract

Aims

We have recently reported that brain-derived extracellular vesicles (BDEVs) from Alzheimer's disease (AD) patients carrying only 300pg of tau propagate tau pathology in aged wild-type mouse brains. To understand BDEV cell types facilitating this phenomenon, we performed quantitative proteomic analysis of BDEVs isolated from AD patients and APP/PS1 mouse brain samples. We further examined EV secretory function of plaque associated microglia in tau propagation mouse model.

Methods

BDEVs were separated from 11 brain samples of AD and control subjects and 6 brain samples of CAST.APP/PS1 and control female mouse at 8 month by discontinuous sucrose gradient ultracentrifugation and subjected to tandem tag mass spectrometry for differentially expressed protein and pathway analysis. Adeno-associated virus containing P301L mutant tau was injected into the entorhinal cortex (EC) of APPNL-G-F mice with or without colony stimulating factor 1 receptor (CSF1R) inhibitor for microglia depletion. Some animals were co-injected with lentivirus to express mEmerald-CD9 specifically in microglia for examining EV secretion in vivo.

Results

Disease associated microglia signature proteins were significantly upregulated in BDEVs with AD patients (APOE, ITGAX and CD63) and APP/PS1 mouse (Itgax) compared to the control. Removal of microglia by CSF1R inhibitor dramatically reduced tau propagation from the EC to the dentate gyrus of hippocampus in APPNL-G-F mouse brains. Interestingly MAC2+ plaque associated microglia secrete significantly more mEmrald+CD9+EVs compared to MAC2- microglia, and possess tau shown by Immuno electron microscope, suggesting pathological tau transfer by those EVs.

Conclusions

Plaque associated microglia may secrete more BDEVs containing tau and may contribute to tau pathology progression in AD.

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DIFFERENTIAL RESPONSES TO AMYLOID BURDEN IN DIVERSE MOUSE GENETIC BACKGROUNDS

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 112
Lecture Time
04:45 PM - 05:00 PM

Abstract

Aims

Mouse models of Alzheimer’s disease (AD) are typically based on a single inbred genetic background, thereby limiting the capacity to reflect the diverse genetics of the human population. We have created a panel of highly diverse Collaborative Cross inbred lines with amyloidogenic mutations to better represent phenotypic diversity in response to amyloid and development of dementia.

Methods

We crossed C57BL/6J mice carrying APPswe, PS1de9, and APOE4 alleles to a panel of five Collaborative Cross strains selected for maximal variation in genes associated with late-onset AD. F1 mice and wild-type F1 controls were aged and brain hemispheres were assessed with RNA-seq and neuropathology. Differential gene expression was analyzed across strains to establish differences and within strains to assess response to amyloid. Transcriptome results were correlated with neuropathology measures and human gene modules from postmortem study cohorts in AMP-AD.

Results

We observed strain-specific differences in key AD-related pathways, including baseline differences in immune factors. In response to amyloid burden, we found variation in both the pathways responding and the degree of response across multiple AD-relevant processes, including immune and metabolic processes. Comparison with human gene modules revealed extensive strain and sex variation correlated with DNA repair and synaptic signaling. Integration with neuropathological outcomes revealed potential differences in cerebral amyloid angiopathy that was correlated with transcriptional signatures.

Conclusions

Expanding the genetic background of mouse models for AD reveals a diversity of baseline states and responses to amyloid, broadening the capacity for mice to model molecular signatures of late-onset AD.

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THE UPPSALA APP DELETION CAUSES STRUCTURALLY DISTINCT ABETA PATHOLOGY AND ALTERED APP PROCESSING IN TRANSGENIC MICE

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 112
Lecture Time
05:00 PM - 05:15 PM

Abstract

Aims

The newly discovered Uppsala APP mutation, a six amino acid deletion within the Aβ sequence, causes early onset Alzheimer’s disease. The mutation alters APP processing, leading to increased formation of mutated Aβ (AβUpp), which rapidly aggregates to form amyloid plaques1. To better understand the development of pathology and the structure of AβUpp plaques, we aimed to study this in vivo.

Methods

Transgenic mice with a combination of the Swedish and Uppsala APP mutations (tg-UppSwe) were generated. APP processing and Aβ pathology was analyzed with Western blot, ELISA, immunostainings and MALDI imaging mass spectrometry. In vivo [11C]PiB- and immuno-PET imaging with brain penetrating variants of Aβ antibodies mAb158 and 3D6 was performed in tg-UppSwe, compared to tg-ArcSwe and tg-Swe mice.

Results

Tg-UppSwe mice displayed increased β-secretase and altered α-secretase cleavage, causing increased AβUpp production, while a normal 40/42 ratio of soluble AβUpp, suggested γ-secretase cleavage to be unaffected. Aβ plaques were diffuse, developed from the age of 8 months and contained exclusively variants of AβUpp42, including AβUpp5-42, similar to human mutation carriers1. In vivo PET imaging revealed that tg-UppSwe, unlike tg-ArcSwe and tg-Swe, was negative for both [11C]PiB and mAb158, while all were positive for 3D6. When crossed with tg-Swe, tg-UppSwe mice displayed more dense-core plaques.

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Conclusions

This study confirms previous findings around the Uppsala APP mutation1 and further suggests that γ-secretase activity is unaffected. Specific structural features of AβUpp aggregates appear to render them unsusceptible to certain antibody interactions in vivo.

1Pagnon de la Vega et al. Science Translational Medicicne 2021;13(606):eabc6184

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SUPER-RESOLUTION STUDIES OF ABETA42 AND ITS PRECURSORS IN NEURONS

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 112
Lecture Time
05:15 PM - 05:30 PM

Abstract

Aims

Our aim is to – at a cellular level – further understand the generation and polymerization of Aβ and its role in AD pathogenesis. Our approach to achieve this aim is to study how Aβ is formed from its precursor APP and explore the different pools of Aβ in subcellular details in neurons by using super-resolution microscopy.

Methods

We used advanced fluorescence microscopes to resolve the subcellular details of neurons, making it possible to visualize even single synaptic vesicles. Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional three-channel imaging, and quantitative image analyses. We also used live cell imaging to study Aβ uptake and transport.

Results

We showed that N- and C-terminal fragments of APP (APP-CTFs) are sorted in early endosomes in soma, and that Aβ42, APP-CTFs and gamma-secretase are all enriched in the presynapse, suggesting that the presynapse is a site of Aβ42 production. In contrast, exogenous Aβ42 was enriched at the plasma membrane of the neuron, endocytosed and trafficked to late endosomes and lysosomes, and eventually accumulated in the soma.

Conclusions

Super-resolution microscopy is a valuable technique for studying Aβ and its precursors at a subcellular level. The presynapse appears to be an important site for Aβ generation, while endocytosed Aβ is transported to somatic endosomal/lysosomal compartments. Further investigations are necessary to characterize the physiological/pathological roles of Aβ in the different pools.

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PRE-RECORDED: CRYO-EM STRUCTURES OF AMYLOID FILAMENTS FROM HUMAN BRAIN

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 112
Lecture Time
05:30 PM - 05:45 PM

PRE-RECORDED: AMYLOID-Β PATHWAY ACROSS TIME AND SPACE IN ALZHEIMER’S DISEASE

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 112
Lecture Time
05:45 PM - 06:00 PM

Abstract

Abstract Body

Amyloid-β (Aβ) as a hallmark of Alzheimer’s disease (AD) pathology and an early component in Alzheimer’s pathophysiology1 had led to the ongoing effort of therapeutic development that targets various species of Aβ. Despite decades of research, however, it is not yet clear what exact part of Aβ pathway — and when and where — confers detrimental effects to brain function and during which stages of the disease. For a structurally and functionally dynamic biochemical pathway, such as the Aβ cycle, the thorough understanding of epoch (temporal) and loci (spatial) of toxic effects of Aβ species will enrich our understanding of the AD pathophysiologic continuum and may provide further insights into therapeutic development. Here, a review of the existing literature of clinical and experimental studies will discuss various components of the Aβ pathway and their biological activities at molecular, cellular, and systematic loci across disease stages and time scale. Understanding Aβ dynamics in space and time may help identify new targets and guide drug development.

1. Hampel H, Hardy J, Blennow K, et al. The Amyloid-β Pathway in Alzheimer's Disease [published online ahead of print, 2021 Aug 30]. Mol Psychiatry. 2021;10.1038/s41380-021-01249-0.
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DISCUSSION

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 112
Lecture Time
06:00 PM - 06:15 PM