Abstract
BackgroundAccumulating evidence indicates that Tau pathology can spread from neuron to neuron by intake and coaggregation of the hyperphosphorylated Tau (p-Tau) seeds with the host neuron protein. Thus, clearance of Tau seeds by immunization with Tau antibodies could provide a potential therapeutic opportunity to block the spread of the pathology in Alzheimer’s disease (AD) and other tauopathies. We report prevention of the seeding and spread of tau pathology with mouse monoclonal antibody 43D against the N-terminal projection domain of Tau (Tau 6–18) in triple-transgenic AD (3 × Tg-AD) mice.MethodsFemale 11- to 12-month-old 3 × Tg-AD mice were intravenously immunized weekly for 6 weeks with 15 μg/injection of mouse monoclonal antibody 43D or with mouse immunoglobulin G as a control. AD p-Tau isolated from a frozen autopsied AD brain was unilaterally injected into the right hippocampus on the day of the second dose of immunization. Tau pathology and its effect on Aβ pathology were assessed by immunohistochemical staining.ResultsWe found that the injection of AD p-Tau into the hippocampus of 11- to 12-month-old 3 × Tg-AD mice time-dependently induced Tau aggregation in the hippocampus and promoted the spread of Tau pathology to the contralateral hippocampus. Tau pathology was observed as early as 6 weeks after AD p-Tau injection. Tau pathology templated by AD p-Tau was thioflavin-S-positive and was about two-fold greater than that seen in naive 18-month-old 3 × Tg-AD mice; Tau pathology in the latter was thioflavin-S-negative. Immunization with Tau antibody 43D dramatically blocked AD p-Tau seeding in the ipsilateral hippocampus and inhibited its propagation to the contralateral side in 3 × Tg-AD mice. Furthermore, AD p-Tau injection enhanced the amyloid plaque load in the ipsilateral side, and immunization with 43D showed a tendency to attenuate it.ConclusionsThese findings indicate that AD p-Tau-injected 3 × Tg-AD mice represent a practical model to study the seeding and spread of Tau pathology, their effect on Aβ pathology, and the effect of Tau immunotherapy on both Tau and Aβ pathologies. Immunization with Tau antibody 43D to Tau 6–18 can prevent the seeding and spread of Tau pathology, making it a potential therapeutic treatment for AD and related tauopathies.
Highlights
Accumulating evidence indicates that Tau pathology can spread from neuron to neuron by intake and coaggregation of the hyperphosphorylated Tau (p-Tau) seeds with the host neuron protein
Alzheimer’s disease (AD) AD abnormally hyperphosphorylated Tau (p-Tau) seeds Tau pathology in a time-dependent manner in 3 × Triple-transgenic Alzheimer’s disease mouse model (Tg-AD) mice In a recent study, we showed that intrahippocampal injection of oligomeric AD p-Tau into the hippocampus of 3-month-old human Tau (h-Tau)-transgenic mice produced spread of Tau pathology in the brain at 11 months after injection [17]
Compared with AD brain extract, the AD p-Tau was highly enriched in hyperphosphorylated Tau as seen on Western blots developed with phospho-Tau antibody PHF-1 (Fig. 1b)
Summary
Accumulating evidence indicates that Tau pathology can spread from neuron to neuron by intake and coaggregation of the hyperphosphorylated Tau (p-Tau) seeds with the host neuron protein. Clearance of Tau seeds by immunization with Tau antibodies could provide a potential therapeutic opportunity to block the spread of the pathology in Alzheimer’s disease (AD) and other tauopathies. In certain pathological conditions, hyperphosphorylated Tau causes the formation of insoluble aggregates that are toxic to neurons [3,4,5,6]. The Tau pathology made up of the p-Tau is a hallmark of several neurodegenerative disorders known as tauopathies, which include frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, Pick disease, Guam Parkinsonism-dementia complex, and chronic traumatic encephalopathy. There are no effective treatments available for AD and related tauopathies
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