In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce...
Transcript of In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce...
![Page 1: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/1.jpg)
Transmission of Misfolded Proteins in
Neurodegenerative Disorders: A Common
Mechanism of Disease Progression
Virginia M.-Y. Lee, Ph.D.
Center for Neurodegenerative Disease Research,
Department of Pathology and Laboratory Medicine,
University of Pennsylvania School of Medicine
Philadelphia, PA
![Page 2: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/2.jpg)
Jucker and Walker, 2013
Aβ
plaques
Tau tangles
α-syn Lewy
bodies
TDP-43
inclusions
Stereotypically Spreading of Disease Pathology as Shared Pathogenic
Mechanism Among Age-related Neurodegenerative Diseases
![Page 3: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/3.jpg)
• Alzheimer’s disease
• Dementia pugilistica
• Down syndrome
• Prion diseases
• Amyotrophic lateral sclerosis/parkinsonism-dementia complex
• Argyophilic grain dementia
• Corticobasal degeneration (CBD)
• Diffuse neurofibrilary tangles with calcification
• Frontotemporal dementia/parkinsonism linked to chromosome-
17 (FTDP-17)
• Hallervorden-Spatz disease
• Nieman-Pick disease type C
• Pick’s disease
• Progressive supranuclear palsy (PSP)
• Subacute sclerosing panencephalitis
• Tangle-predominant Alzheimer’s disease
A Large Number of Neurodegenerative Diseases
Contain Tau Pathology
![Page 4: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/4.jpg)
• Parkinson’s disease
• Parkinson’s disease with dementia
• Dementia with Lewy bodies
• Multisystem atrophy
• Alzheimer’s disease
Major Neurodegenerative Diseases with α-Synuclein Pathology
![Page 5: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/5.jpg)
The Transmission Hypothesis: Can
misfolded neurodegenerative disease
proteins initiate and induce the cell-to-cell
spread of pathology in mouse models?
The Strain Hypothesis: Do
pathological strains exist in
neurodegenerative disease proteinopathies
that could potentially explain clinical
diversity?
Working Hypotheses
![Page 6: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/6.jpg)
Inoculation of Synthetic Mouse α-Syn PFFs into
the Dorsal Striatum of Non-transgenic Mice
Mouse α-syn pffs
![Page 7: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/7.jpg)
Intrastriatal injection of mouse α-Syn PFFs in Wildtype
Mice Recruit Endogenous α-Syn to form LBs and LNs
Luk et al., Science, 2012
![Page 8: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/8.jpg)
α-Syn pathology in SNpc leads to a progressive
loss of DA neurons
![Page 9: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/9.jpg)
SNpc ɑ-Syn Pathology Leads to Impaired Balance
and Motor Co-ordination
![Page 10: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/10.jpg)
AT8 AD-tau:
Intracerebral injections of AD-tau induces more abundant tau pathology
than synthetic tau PFFs in non-Tg mice
Guo et al., JEM, 2016
![Page 11: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/11.jpg)
Cell-to-Cell Transmission of Tau Pathology throughout
the Neuroanatomical Connectome of Wildtype Mice
![Page 12: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/12.jpg)
1 mpi p409-410
Formation of de-novo TDP-43 pathology in CaMKIIa-TDP-43NLSm mice
injected with FTLD-TDP-43 extracts
Porta et al., Nat Comm 2018
![Page 13: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/13.jpg)
TDP-43 pathology spreading to rostral deep brain nuclei
and white matter tracts over time post-injection
Porta et al., Nat Comm. 2018
![Page 14: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/14.jpg)
• α-Syn PFFs initiate conversion of endogenous α-
Syn and their accumulation into Lewy-body and
Lewy neurite-like inclusions in animal models.
• α-Syn inclusions drives the selective loss of SNpc
DA neurons, resulting in behavioral impairments
reminiscent of human PD
• AD-tau but not synthetic tau fibrils induce
neurofibrillary tangle-like pathology in wildtype mice.
• FTLD-TDP enriched lysates induce the formation
and propagation of TDP-43 pathology in TDP-43
transgenic mice
Summary of Misfolded Neurodegenerative
Disease Protein Transmission
![Page 15: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/15.jpg)
The Transmission Hypothesis: Can the
spread of disease pathology be mediated by
misfolded neurodegenerative disease
proteins in mouse models?
The Strain Hypothesis: Do pathological
strains exist in neurodegenerative disease
proteinopathies that could potentially explain
clinical diversity?
Working Hypotheses
![Page 16: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/16.jpg)
Modified from Riedl et al., 2014
Tan et al., Acta Neuropath. Communications,
2013
B
A
C
D
Cortical Pathology
Classification of FTLD-TDP based on genetic,
clinical correlations and pTDP-43 distribution
![Page 17: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/17.jpg)
Coiled Bodies
Tau Pathology In CBD, PSP, AD & Related Tauopathies
![Page 18: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/18.jpg)
HP/Ctx, 3 months post-injection, IHC for AT8 (pS202/T205)
AD case 1 (1ug/site) n=3
CBD case 1 (1ug/site) n=4
PSP case 1 (0.7ug/site) n=4
One-way ANOVA with Tukey post-hoc (*p<0.05, **p<0.01, ***p<0.001)
Human tau strains have different
seeding potencies in non-Tg mice
Narasimhan et al., J. Neurosci, 2017
![Page 19: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/19.jpg)
Oligodendrocytes Astrocytes
Irwin et al (2014) Acta Neuropathologica
Kouri et al (2011) Nature Rev Neurology
Human CBD Human CBD Human PSP
3 months post-injection
CBD case 1 (1ug/site) n=4
PSP case 1 (0.7ug/site) n=4
CBD-tau, PSP-tau but not AD-tau induced glia
tau pathology, recapitulating the human
neuropathology
![Page 20: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/20.jpg)
.
Ab plaque
burden
Examine pathology
at: 1 mo.p.i.
3 mo.p.i.
6 mo.p.i.
9 mo.p.i.
Injection of AD-Tau into Ab-bearing mice to generate a AD mouse model with Ab plaques and neurofibrillary tangles
He et al., Nat Med, 2018
![Page 21: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/21.jpg)
AD-WT (15mo) @ 1mo.p.i. AD-APP KI (NL-F, 15mo) @ 1mo.p.i. AD-5xFAD (8mo) @ 1mo.p.i.
AT8+ dystrophic neurites AT8- dystrophic neurites
NAB228)/AT8/DAPI
Induced NP-tau were comprised of endogenous mouse tau, rather than injected human tau
Induced NP-tau were PHF-like structure in dystrophic
neurites surrounding Ab plaques
APP-N/Tau(2295) AT8
AD brain stained with PHF-1
Tau aggregates are present in the dystrophic neurites surrounding Ab plaques at very early seeding stages
He et al., Nat Med, 2018
![Page 22: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/22.jpg)
AD
-WT
A
D-5
xF
AD
(8m
o)
IHC: AT8
1 m.p.i. 3 m.p.i. 9 m.p.i.
He et al., Nat. Med., 2018
Neuritic plaque formation precedes and might even
initiate NFT formation
![Page 23: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/23.jpg)
Synucleinopathies
PD
Without dementia
With dementia
Younger onset, purer LB pathologies, longer
onset to dementia, longer disease duration
Older onset, more frequent co-morbid AD pathologies, shorter
onset to dementia, more malignant disease course
DLB
Low NFTs
Abundant NFTs
Multiple system atrophy
‘1 year rule’
α-syn inclusions
predominantly in
oligodendrocytes
Giasson and Lee, 2003
Can Unique α-Syn Strains from Synucleinopathy
Brains be Demonstrated?
![Page 24: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/24.jpg)
P1 de novo
Non-Tg neurons (18 d post-transduction)
(p-α-Syn)
1% Triton-extracted
Guo et al., Cell, 2013
Strain A
Strain B
P6-P7
P2
P3
P4
P5
10%
10%
10%
10%
10%
(p-Tau)
Generation of different strains of α-syn preformed fibrils (PFFs) with distinct seeding properties
![Page 25: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/25.jpg)
Covell et al., NAM 2017
AutopsyID npDx1 Region
2004-027 AD-DLB SN
2005-274 AD-DLB Fro
2008-182 AD-DLB Hip
2006-072 DLB SN
2008-208 DLB Fro
2009-200 DLB Hip
2009-071 PD/D Fro
2010-042 PD/D SN
2012-049 PD/D Hip
2000-243 MSA-C Cereb
2006-005 MSA-C SN
2007-198 MSA-C Hip
2010-195 MSA-C Fro
2002-117 MSA-P Hip
2007-186 MSA-P SN
2012-181 MSA-P Fro
Syn7015 differentiates between LBs and GCIs in MSA
![Page 26: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/26.jpg)
Pathological α-Syn in GCIs and LBs have very distinct conformational
and biochemical properties
![Page 27: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/27.jpg)
GCI-α-Syn is ~1000 fold more potent than LB-α-syn to induce
α-syn pathology in primary oligodendrocyte cultures
Peng et al., Nature, 2018
![Page 28: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/28.jpg)
GCI-α-Syn is also ~1000 fold more potent than LB-α-syn to induce α-syn
pathology in primary neuronal cultures and QBI cells
![Page 29: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/29.jpg)
Passage α-syn PFFs in oligodendrocytes but not in
neurons or QBI cells could increase its potency
α-Syn
Intracellular millieu of oligodendrocytes converts α-Syn PFFs to GCI-α-Syn strain
![Page 30: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/30.jpg)
Once GCI-α-Syn is generated, passage in primary neurons
could maintain its high potency
Peng et al., Nature, 2018
![Page 31: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/31.jpg)
• GCI-α-Syn and LB-α-Syn define distinct
pathological α-Syn strains found in MSA and
PD/PDD/DLB brains
• GCI-α-Syn is 1,000-fold more potent than LB-α-
Syn in seeding α-Syn aggregation.
• The seeding properties of GCI-α-Syn and LB-α-
Syn show no cell type preference.
• Intracellular oligodendrocyte environment
converts misfolded α-Syn into a GCI-like strain.
• Neuron environment cannot convert GCI-α-Syn
to a LB-like strain.
Summary of MSA and PD/PDD brain-
derived strains
![Page 32: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/32.jpg)
• Brain-derived tau aggregates from tauopathy brains
induce progressive cell type-specific cell-to-cell spread of
tau tangles in wildtype and Aβ plaque-bearing mice that
recapitulate their human disease counterparts.
• Brain-derived α-Syn aggregates from synucleinopathy
brains also induce progressive cell type specific cell-to-
cell spread of LB and GCI pathology in wildtype mice
recapitulating PD/PDD/DLB and MSA respectively.
• Brain-derived TDP-43 aggregates from FTLD-TDP brains
induce progressive spread of TDP-43 aggregates in
transgenic mice expressing TDP-43-NLS.
• Transmission of neurodegenerative disease protein
strains represent a common mechanism of disease
progression and pathogenesis in neurodegenerative
diseases.
Conclusions
![Page 33: In vivo transmission of α-Syn pathology · 2019-05-08 · Virginia M.-Y. Lee, Ph.D. ... induce progressive cell type-specific cell-to-cell spread of tau tangles in wildtype and Aβ](https://reader035.fdocument.pub/reader035/viewer/2022062917/5ece2b4fee11c142a623d808/html5/thumbnails/33.jpg)
• Zhuohao He
• Chao Peng
• Sneha Narasimhan
• Silvia Porta
• Jing Guo
• Kelvin Luk
• Linda Kwong
• Bin Zhang
• John Trojanowski
Supported by grants from NIH/NIA/NINDS, the Ware Alzheimer’s Program,
MJFF, and the families of our patients.
• John Robinson
• Clark Restrepo
• Coraima Medellin
• Rose Pitkin
• Matt Byrnes
• Dawn Riddle
• Ronal Gathagan
• Yan Xu
Acknowledgements