Dataset Information

Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models.

ABSTRACT: Diabetes mellitus (DM) is one of the most devastating diseases that currently affects the aging population. Recent evidence indicates that DM is a risk factor for many brain disorders, due to its direct effects on cognition. New findings have shown that the microtubule-associated protein tau is pathologically processed in DM; however, it remains unknown whether pathological tau modifications play a central role in the cognitive deficits associated with DM. To address this question, we used a gain-of-function and loss-of-function approach to modulate tau levels in type 1 diabetes (T1DM) and type 2 diabetes (T2DM) mouse models. Our study demonstrates that tau differentially contributes to cognitive and synaptic deficits induced by DM. On one hand, overexpressing wild-type human tau further exacerbates cognitive and synaptic impairments induced by T1DM, as human tau mice treated under T1DM conditions show robust deficits in learning and memory processes. On the other hand, neither a reduction nor increase in tau levels affects cognition in T2DM mice. Together, these results shine new light onto the different molecular mechanisms that underlie the cognitive and synaptic impairments associated with T1DM and T2DM.

SUBMITTER: Trujillo-Estrada L

PROVIDER: S-EPMC6516168 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models.

Trujillo-Estrada Laura L Nguyen Cassidy C da Cunha Celia C Cai Lena L Forner Stefania S Martini Alessandra C AC Ager Rahasson R RR Prieto Gilberto Aleph GA Cotman Carl W CW Baglietto-Vargas David D LaFerla Frank M FM

Aging cell 20190227 3

Diabetes mellitus (DM) is one of the most devastating diseases that currently affects the aging population. Recent evidence indicates that DM is a risk factor for many brain disorders, due to its direct effects on cognition. New findings have shown that the microtubule-associated protein tau is pathologically processed in DM; however, it remains unknown whether pathological tau modifications play a central role in the cognitive deficits associated with DM. To address this question, we used a gai ...[more]

PMID: 30809950

Similar Datasets

Project description:Clinical and neuropathological studies have shown that tau pathology better correlates with the severity of dementia than amyloid plaque burden, making tau an attractive target for the cure of Alzheimer's disease. We have explored whether passive immunization with the 12A12 monoclonal antibody (26-36aa of tau protein) could improve the Alzheimer's disease phenotype of two well-established mouse models, Tg2576 and 3xTg mice. 12A12 is a cleavage-specific monoclonal antibody which selectively binds the pathologically relevant neurotoxic NH226-230 fragment (i.e. NH2htau) of tau protein without cross-reacting with its full-length physiological form(s). We found out that intravenous administration of 12A12 monoclonal antibody into symptomatic (6 months old) animals: (i) reaches the hippocampus in its biologically active (antigen-binding competent) form and successfully neutralizes its target; (ii) reduces both pathological tau and amyloid precursor protein/amyloidβ metabolisms involved in early disease-associated synaptic deterioration; (iii) improves episodic-like type of learning/memory skills in hippocampal-based novel object recognition and object place recognition behavioural tasks; (iv) restores the specific up-regulation of the activity-regulated cytoskeleton-associated protein involved in consolidation of experience-dependent synaptic plasticity; (v) relieves the loss of dendritic spine connectivity in pyramidal hippocampal CA1 neurons; (vi) rescues the Alzheimer's disease-related electrophysiological deficits in hippocampal long-term potentiation at the CA3-CA1 synapses; and (vii) mitigates the neuroinflammatory response (reactive gliosis). These findings indicate that the 20-22 kDa NH2-terminal tau fragment is crucial target for Alzheimer's disease therapy and prospect immunotherapy with 12A12 monoclonal antibody as safe (normal tau-preserving), beneficial approach in contrasting the early Amyloidβ-dependent and independent neuropathological and cognitive alterations in affected subjects.

Dataset Information

Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models.

Publications

Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets