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Cell-to-Cell Spread of Pathological Tau
Virginia M.-Y. Lee, Ph.D.Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine,
University of Pennsylvania School of MedicinePhiladelphia, PA, USA
Alzforum WebinarApril 8, 2016
+dPBS (control) +tau pffs
1% Triton-X 100 AT8/DAPI
Intracellular tau fibrillization seeded by exogenous tau preformed fibrils in P301S tau-overexpressing neurons
Strain A
Strain B
(p-α-syn) (p-tau)
1% Triton-X100 Guo et al., 2013
Tau pathology induced by some strains of α-syn preformed fibrils in non-Tg neurons
Jucker and Walker, 2013
Aβ plaques
Tau tangles
α-syn Lewybodies
TDP-43inclusions
Stereotypically Spreading of Disease Pathology as Shared Pathogenic Mechanism Among Age-related Neurodegenerative Diseases
Locus Coeruleus
HippocampusHypothalamus
Amygdala
Forebrain (BNST)Thalamus
The nucleus Paragigantocellularis (PGi) Prepositus hypoglossi (PrH)
1785-1mo-020-AT8-PGi-2
1749-2wk-080-AT8-PGi 2175-1mo-020-AT8-PrH
2297-3mo-040-AT8-PrH
Tau Pathology Propagated From LC
Bregma 0.98 mm
Bregma -1.22 mm
Bregma -2.18 mm
Bregma -2.92 mm
Bregma -4.48 mm
Bregma -5.52 mm
Hippocampus injection
1 month 3 month 6 month
Bregma -2.92 mm
Bregma -4.48 mm
Bregma -5.52 mm
Bregma -2.18 mm
Bregma 1.98 mm
Bregma 0.38 mm
1 month 3 month 9 month
Striatum and cortex injection
Tau Spreading in Mouse Models Follows the Neuroanatomic Connectome
Iba et al., J Neurosci, 2013
• 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• Pathological aging related tauopathy or PART (formerly tangle-
predominant senile dementia ort TPSD)
Tau Pathology in Different Neurodegenerative Diseases may Represent Different Tau Strains
Injections of CBD-Tau and AD/DS-Tau in PS19 Mice Demonstrate strain Properties that Recapitulate Their Human Counterparts
Boluda et al., Acta Neuropath, 2015
Guo JL and Lee, VMY Nat. Med, 2014.
Mechanisms of Cell-to Cell Transmission of Pathological Disease Proteins
Holmes et al. PNAS 2013
Uptake of Transmitted Disease Proteins By Macropinocytosis
Tau aggregates bind HSPGs for uptake
clathrin
rece
ptor
Holmes et al. PNAS 2013
Tau Binds HSPG “Receptors” to Enter Cells
Pooler et al, Acta Neuropath Comm 2015
Dramatic Acceleration of Tau Propagation in The Presence of Aβ Amyloid Deposits
• Elucidate the biology of human tauopathy strains:1. Develop in vitro and in vivo models of different tau strains to model
different human tauopathies in transgenic and wild type mice2. Determine the biochemical and biophysical properties of synthetic tau
strains, human tau seeded-strains and human brain-derived tauopathy strains
3. Elucidate the molecular mechanisms of cell-type specific tau strains in neurons and glia
• Elucidate the molecular mechanisms of tau pathology spreading:
1. Determine how misfolded tau are taken up into neurons and glia2. Identify the mechanisms of templated recruitment of endogenous tau
within neurons and glia3. Understand how misfolded tau are released from neurons and glia
• Validate tau pathology spreading in animal models that recapitulate the progression of human tauopathies.
• Identify new targets and therapies for treatment of tauopathies based on tau pathology spreading
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