TY - JOUR
T1 - Accumulation of C-terminal cleaved tau is distinctly associated with cognitive deficits, synaptic plasticity impairment, and neurodegeneration in aged mice
AU - Loon, Anjanet
AU - Zamudio, Frank
AU - Sanneh, Awa
AU - Brown, Breanna
AU - Smeltzer, Shayna
AU - Brownlow, Milene L.
AU - Quadri, Zainuddin
AU - Peters, Melinda
AU - Weeber, Edwin
AU - Nash, Kevin
AU - Lee, Daniel C.
AU - Gordon, Marcia N.
AU - Morgan, Dave
AU - Selenica, Maj Linda B.
N1 - Publisher Copyright:
© 2021, American Aging Association.
PY - 2022/2
Y1 - 2022/2
N2 - C-terminal cleaved tau at D421 (∆D421-tau) accumulates in the brains of Alzheimer’s disease (AD) patients. However, it is unclear how tau truncation, an understudied tau post-translational modification, contributes to AD pathology and progression. Utilizing an adeno-associated virus (AAV) gene delivery-based approach, we overexpressed full-length tau (FL-tau) and ∆D421-tau in 4- and 12-month-old mice for 4 months to study the neuropathological impact of accumulation in young adult (8-month) and middle-aged (16-month) mice. Overall, we show that independent of the tau species, age was an important factor facilitating tau phosphorylation, oligomer formation, and deposition into silver-positive tangles. However, mice overexpressing ∆D421-tau exhibited a distinct phosphorylation profile to those overexpressing FL-tau and increased tau oligomerization in the middle-age group. Importantly, overexpression of ∆D421-tau, but not FL-tau in middle-aged mice, resulted in pronounced cognitive impairments and hippocampal long-term potentiation deficits. While both FL-tau and ∆D421-tau induced neuronal loss in mice with age, ∆D421-tau led to significant neuronal loss in the CA3 area of the hippocampus and medial entorhinal cortex compared to FL-tau. Based on our data, we conclude that age increases the susceptibility to neuronal degeneration associated with ΔD421-tau accumulation. Our findings suggest that ΔD421-tau accumulation contributes to synaptic plasticity and cognitive deficits, thus representing a potential target for tau-associated pathologies.
AB - C-terminal cleaved tau at D421 (∆D421-tau) accumulates in the brains of Alzheimer’s disease (AD) patients. However, it is unclear how tau truncation, an understudied tau post-translational modification, contributes to AD pathology and progression. Utilizing an adeno-associated virus (AAV) gene delivery-based approach, we overexpressed full-length tau (FL-tau) and ∆D421-tau in 4- and 12-month-old mice for 4 months to study the neuropathological impact of accumulation in young adult (8-month) and middle-aged (16-month) mice. Overall, we show that independent of the tau species, age was an important factor facilitating tau phosphorylation, oligomer formation, and deposition into silver-positive tangles. However, mice overexpressing ∆D421-tau exhibited a distinct phosphorylation profile to those overexpressing FL-tau and increased tau oligomerization in the middle-age group. Importantly, overexpression of ∆D421-tau, but not FL-tau in middle-aged mice, resulted in pronounced cognitive impairments and hippocampal long-term potentiation deficits. While both FL-tau and ∆D421-tau induced neuronal loss in mice with age, ∆D421-tau led to significant neuronal loss in the CA3 area of the hippocampus and medial entorhinal cortex compared to FL-tau. Based on our data, we conclude that age increases the susceptibility to neuronal degeneration associated with ΔD421-tau accumulation. Our findings suggest that ΔD421-tau accumulation contributes to synaptic plasticity and cognitive deficits, thus representing a potential target for tau-associated pathologies.
KW - Age
KW - Cognition
KW - Entorhinal cortex
KW - Full-length tau
KW - LTP
KW - Neurodegeneration
KW - Tauopathy
KW - Truncated tau
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U2 - 10.1007/s11357-021-00408-z
DO - 10.1007/s11357-021-00408-z
M3 - Article
C2 - 34410588
AN - SCOPUS:85113430090
SN - 2509-2715
VL - 44
SP - 173
EP - 194
JO - GeroScience
JF - GeroScience
IS - 1
ER -