Presentation made April 8, 2016 at the live webinar hosted by Alzforum - http://www.alzforum.org/webinars/webinar-pathogenic-protein-spread-lets-think-again

1. 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 Medicine
Philadelphia, PA, USA
Alzforum Webinar
April 8, 2016

2. +dPBS (control) +tau pffs
1% Triton-X 100
AT8/DAPI
Intracellular tau fibrillization seeded by exogenous tau
preformed fibrils in P301S tau-overexpressing neurons

3. 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

4. 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

5. Locus Coeruleus
Hippocampus
Hypothalamus
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

6. 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

7. • 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

8. 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

9. Guo JL and Lee, VMY Nat. Med, 2014.
Mechanisms of Cell-to Cell Transmission
of Pathological Disease Proteins

10. Holmes et al. PNAS 2013
Uptake of Transmitted Disease Proteins
By Macropinocytosis

11. Tau aggregates bind HSPGs for uptake
clathrin
receptor
Holmes et al. PNAS 2013
Tau Binds HSPG “Receptors” to Enter Cells

12. Pooler et al, Acta Neuropath Comm 2015
Dramatic Acceleration of Tau Propagation in
The Presence of Aβ Amyloid Deposits

13. • 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 mice
2. 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 glia
2. Identify the mechanisms of templated recruitment of endogenous tau
within neurons and glia
3. 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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