Abstract
Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer's disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and divergent trajectories. To study the divergent physiological properties of tau variants on a uniform immunogenetic background, we created somatic transgenesis CNS models of tauopathy utilizing neonatal delivery of adeno-associated viruses expressing wild-type (WT) or mutant tau in non-transgenic mice. We selected four different tau variants-WT tau associated with AD, P301L mutant tau associated with frontotemporal dementia (FTD), S320F mutant tau associated with Pick's disease and a combinatorial approach using P301L/S320F mutant tau. CNS-targeted expression of WT and P301L mutant tau results in robust tau hyperphosphorylation without tangle pathology, gradually developing age-progressive memory deficits. In contrast, the S320F variant, especially in combination with P301L, produces an AD-type tangle pathology, focal neuroinflammation and memory impairment on an accelerated time scale. Using the doubly mutated P301L/S320F tau variant, we demonstrate that combining different mutations can have an additive effect on neuropathologies and associated co-morbidities, possibly hinting at involvement of unique functional pathways. Importantly, we also show that overexpression of wild-type tau as well as an FTD-associated tau variant can lead to cognitive deficits even in the absence of tangles. Together, our data highlights the synergistic neuropathologies and associated cognitive and synaptic alterations of the combinatorial tau variant leading to a robust model of tauopathy.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3255-3269 |
| Number of pages | 15 |
| Journal | Human molecular genetics |
| Volume | 28 |
| Issue number | 19 |
| DOIs | |
| State | Published - Oct 1 2019 |
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ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)
Cite this
Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy. / Koller, Emily J.; Gonzalez De La Cruz, Elsa; Machula, Timothy; Ibanez, Kristen R.; Lin, Wen Lang; Williams, Tosha; Riffe, Cara J.; Ryu, Daniel; Strang, Kevin H.; Liu, Xuefei; Janus, Christopher; Golde, Todd E.; Dickson, Dennis; Giasson, Benoit I.; Chakrabarty, Paramita.
In: Human molecular genetics, Vol. 28, No. 19, 01.10.2019, p. 3255-3269.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy
AU - Koller, Emily J.
AU - Gonzalez De La Cruz, Elsa
AU - Machula, Timothy
AU - Ibanez, Kristen R.
AU - Lin, Wen Lang
AU - Williams, Tosha
AU - Riffe, Cara J.
AU - Ryu, Daniel
AU - Strang, Kevin H.
AU - Liu, Xuefei
AU - Janus, Christopher
AU - Golde, Todd E.
AU - Dickson, Dennis
AU - Giasson, Benoit I.
AU - Chakrabarty, Paramita
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer's disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and divergent trajectories. To study the divergent physiological properties of tau variants on a uniform immunogenetic background, we created somatic transgenesis CNS models of tauopathy utilizing neonatal delivery of adeno-associated viruses expressing wild-type (WT) or mutant tau in non-transgenic mice. We selected four different tau variants-WT tau associated with AD, P301L mutant tau associated with frontotemporal dementia (FTD), S320F mutant tau associated with Pick's disease and a combinatorial approach using P301L/S320F mutant tau. CNS-targeted expression of WT and P301L mutant tau results in robust tau hyperphosphorylation without tangle pathology, gradually developing age-progressive memory deficits. In contrast, the S320F variant, especially in combination with P301L, produces an AD-type tangle pathology, focal neuroinflammation and memory impairment on an accelerated time scale. Using the doubly mutated P301L/S320F tau variant, we demonstrate that combining different mutations can have an additive effect on neuropathologies and associated co-morbidities, possibly hinting at involvement of unique functional pathways. Importantly, we also show that overexpression of wild-type tau as well as an FTD-associated tau variant can lead to cognitive deficits even in the absence of tangles. Together, our data highlights the synergistic neuropathologies and associated cognitive and synaptic alterations of the combinatorial tau variant leading to a robust model of tauopathy.
AB - Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer's disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and divergent trajectories. To study the divergent physiological properties of tau variants on a uniform immunogenetic background, we created somatic transgenesis CNS models of tauopathy utilizing neonatal delivery of adeno-associated viruses expressing wild-type (WT) or mutant tau in non-transgenic mice. We selected four different tau variants-WT tau associated with AD, P301L mutant tau associated with frontotemporal dementia (FTD), S320F mutant tau associated with Pick's disease and a combinatorial approach using P301L/S320F mutant tau. CNS-targeted expression of WT and P301L mutant tau results in robust tau hyperphosphorylation without tangle pathology, gradually developing age-progressive memory deficits. In contrast, the S320F variant, especially in combination with P301L, produces an AD-type tangle pathology, focal neuroinflammation and memory impairment on an accelerated time scale. Using the doubly mutated P301L/S320F tau variant, we demonstrate that combining different mutations can have an additive effect on neuropathologies and associated co-morbidities, possibly hinting at involvement of unique functional pathways. Importantly, we also show that overexpression of wild-type tau as well as an FTD-associated tau variant can lead to cognitive deficits even in the absence of tangles. Together, our data highlights the synergistic neuropathologies and associated cognitive and synaptic alterations of the combinatorial tau variant leading to a robust model of tauopathy.
UR - http://www.scopus.com/inward/record.url?scp=85075109050&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075109050&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddz151
DO - 10.1093/hmg/ddz151
M3 - Article
C2 - 31261380
AN - SCOPUS:85075109050
VL - 28
SP - 3255
EP - 3269
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 19
ER -