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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