braak and braak - university of washington
TRANSCRIPT
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Consequences of tau expression in the entorhinal cortex: Synaptic Propagation of tau and synaptic
degeneration
Brad Hyman MDPhDMass General Hospital, Boston
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Braak and Braak
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Hyman 1986
Tau P301L
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Generation of EC / perforantpathway transgenic line
Neuropsin promoter tTAActivator transgeneNeuropsin promoter tTAActivator transgene
Yasuda and Mayford 2006
X
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Reporter genes reveal exquisite anatomic specificity of neuropsin
promoter mice
dgdg
ECEC
Perf path terminals
dg
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Generation of rTauP301L EC line
tetO Tau P301LResponder transgene
tetO Tau P301LtetO Tau P301LResponder transgene
Neuropsin promoter tTAActivator transgeneNeuropsin promoter tTAActivator transgene
Yasuda and Mayford 2006
X
Santa Cruz et al 2005
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hTau ICC shows transgene in Entorhinal and perforant pathway terminal zone at 3 months of age
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12 mo 18 mo 24 mo
12 mo 18 mo 24 mo
Alz50 Iba1
A
B
C
Degeneration of the terminal zone of the perforant pathway
Microglial activation
HT7
PHF1
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Human tau protein is present in cells with little or no human tau mRNAAs determined by double immunohistochemistry/in situfollowed by laser capture microdissection and qPCR for human tau
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rTauEC mice: Preliminary results of transgene suppression
18 months3 or 6 months with Dox
3 or 6 months without Dox
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Propagation of tau pathology blocked by tau suppression
CA1
CA3
CA1
CA3GL GL
CA1
CA3GL
CA1
CA3
Alz50, 24 m
PHF1, 24 m
Gallyas, 24 m
GL
Alz50, 18 m
A B
0
100
200
300
400
500
18 21 24
dox from 18mdox from 21mno dox
Alz50‐po
sitiv
e ne
uron
s in
DG granu
lar layer
C D
E
*
Propagation blocked to some extent by tau suppression
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Transgene suppression ameliorates neuronal loss as well
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Loss of perforant path terminals leads to synaptic dysfunction and plasticity
response
Suppression of transgene leads to partial blockade of tau
propagation and recovery of plasticity phenotype
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Deafferentation: Synaptic loss specifically in the perforant pathway terminal zone at 24
months
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Hyman 1987
Reinnervation of the perforant pathway terminal zone in Alzheimer disease
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50 um
*
*
*
A
B
AChE staining reveals sprouting into the middle molecular layer
Recovery by transgenesuppression
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Mechanisms of neurodegeneration: implications of the rTauEC line
1. Propagation of misfolded tau across neural systems, leading to propagation of inclusions across neural systems• Human and mouse tau co‐aggregate in these inclusions• Mechanism of propagation still uncertain – toxic species unknown
2. Suppression of tau transgene leads to a delay (or reversal?) in propagation phenotype
3. Neuronal loss appears to be a late phenomenon4. Synaptic loss, though modest, is sufficient to initiate a classic plasticity
sprouting response5. We speculate that the propagation of tau, deafferentation, and altered
plasticity lead to progressive neural system failure that in some ways is analogous to the progressive neuropathological changes in AD
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Massachusetts General Hospital
Alix DeCalignonManuela PolydoroTeresa Gomez‐Isla
Tara Spires
Support: AHAF, AFAR NIHAlzheimer Association
Acknowledgements
Karen AsheGeorge Carlson
N Sahara
Collaborators