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Early active immunization with A?3-10-KLH vaccine reduces tau phosphorylation in the hippocampus and protects cognition of mice.

ABSTRACT: Active and passive anti-A? immunotherapies have successfully been used for the prevention and treatment of Alzheimer's disease animal models. However, clinical use of these immunotherapies is not effective, because the vaccination is administered too late. At 1 month of age, 100 ?L of A?3-10-KLH peptide (vaccine, 2 ?g/?L) was subcutaneously injected into the neck of an amyloid precursor protein/presenilin-1/tau transgenic (3×Tg-AD) mouse model. A?3-10-KLH peptide was re-injected at 1.5, 2.5, 3.5, 4.5, 5.5, and 6.5 months of age. Serum levels of A? antibody were detected by enzyme-linked immunosorbent assay, while spatial learning and memory ability were evaluated by Morris water maze. Immunohistochemistry was used to detect total tau with HT7 and phosphorylated tau with AT8 (phosphorylation sites Ser202 and Thr205) and AT180 (phosphorylation site Thr231) antibodies in the hippocampus. In addition, western blot analysis was used to quantify AT8 and AT180 expression in the hippocampus. The results showed that after vaccine injection, mice produced high levels of A? antibody, cognitive function was significantly improved, and total tau and phosphorylated tau levels were significantly reduced. These findings suggest that early active immunization with A?3-10-KLH vaccine can greatly reduce tau phosphorylation, thereby mitigating the cognitive decline of 3×Tg-AD mice. This study was approved by the Animal Ethics Committee of China Medical University, China (approval No. 103-316) on April 2, 2016.

SUBMITTER: Wang JC

PROVIDER: S-EPMC6921334 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Early active immunization with Aβ3-10-KLH vaccine reduces tau phosphorylation in the hippocampus and protects cognition of mice.

Wang Jin-Chun JC Zhu Kun K Zhang Hui-Yi HY Wang Guo-Qing GQ Liu Hui-Ying HY Cao Yun-Peng YP

Neural regeneration research 20200301 3

Active and passive anti-Aβ immunotherapies have successfully been used for the prevention and treatment of Alzheimer's disease animal models. However, clinical use of these immunotherapies is not effective, because the vaccination is administered too late. At 1 month of age, 100 μL of Aβ3-10-KLH peptide (vaccine, 2 μg/μL) was subcutaneously injected into the neck of an amyloid precursor protein/presenilin-1/tau transgenic (3×Tg-AD) mouse model. Aβ3-10-KLH peptide was re-inj ...[more]

PMID: 31571664

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Project description:BackgroundAccumulation of hyperphosphorylated tau protein is a histopathological hallmark of Alzheimer's disease (AD) and related tauopathies. Currently, there is no effective treatment available for these progressive neurodegenerative diseases. In recent years, tau immunotherapy has shown great potential in animal models. We report the effect of immunization with tau antibodies 43D against tau 6-18 and 77E9 against tau 184-195 on tau and amyloid-β (Aβ) pathologies and cognition in triple-transgenic (3×Tg)-AD mice at mild to moderate stages of the disease.MethodsWe immunized 12-month-old female 3×Tg-AD mice with two to six or seven intravenous weekly doses of 15 μg of mouse monoclonal antibody 43D, 77E9, a combination of one-half dose each of 43D and 77E9, or as control of mouse immunoglobulin G (IgG). Age-matched wild-type mice treated with mouse IgG or a mixture of 43D and 77E9 were also used as controls. The effect of immunization with tau antibodies on tau and Aβ pathologies was assessed by Western blot and immunofluorescence analysis, and the effect on cognition was analyzed by using Morris water maze, one-trial novel object recognition, and novel object location tasks.ResultsWe found that two doses of 43D and 77E9 reduced total tau but had no significant impact on hyperphosphorylation of tau. However, six doses of 43D reduced levels of both total tau and tau hyperphosphorylated at Ser262/356 and Ser396/404 sites in the hippocampus. Importantly, both 43D and 77E9 antibodies rescued spatial memory and short-term memory impairments in 3×Tg-AD mice. The beneficial effect of 43D and 77E9 antibodies on cognitive performance was sustained up to 3 months after the last dose. Six doses of immunization with 43D also decreased amyloid precursor protein (APP) level in CA1 and amyloid plaques in subiculum, and showed a trend toward reducing Aβ40 and Aβ42 in the forebrain. Immunization with 43D increased levels of complement components C1 and C9 and resulted in activation of microglia, especially surrounding Aβ plaques.ConclusionsThese findings suggest the potential of passive immunization targeting proximal N-terminal domain tau 6-18 as a disease-modifying approach to AD and related tauopathies.

Project description:ObjectiveTo examine the cross-sectional associations between regional tau, β-amyloid (Aβ), and cortical thickness and neuropsychological function across the preclinical and clinical spectrum of Alzheimer disease (AD).MethodsWe included 106 participants from the Swedish Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study, of whom 33 had preclinical AD (Aβ-positive cognitively normal individuals), 25 had prodromal AD (Aβ-positive mild cognitive impairment), and 48 had probable AD dementia. All underwent [18F]flortaucipir (tau) and structural MRI (cortical thickness), and 88 of 106 underwent [18F]flutemetamol (Aβ) PET. Linear regression models adjusted for age, sex, and education were performed to examine associations between 7 regions of interest and 7 neuropsychological tests for all 3 imaging modalities.ResultsIn preclinical AD, [18F]flortaucipir, but not [18F]flutemetamol or cortical thickness, was associated with decreased global cognition, memory, and processing speed (range standardized β = 0.35-0.52, p < 0.05 uncorrected for multiple comparisons). In the combined prodromal AD and AD dementia group, both increased [18F]flortaucipir uptake and reduced cortical thickness were associated with worse performance on a variety of neuropsychological tests (most regions of interest survived correction for multiple comparisons at p < 0.05), while increased [18F]flutemetamol uptake was specifically associated with lower scores on a delayed recall memory task (p < 0.05 uncorrected for multiple comparisons). The strongest effects for both [18F]flortaucipir and cortical thickness on cognition were found in the lateral and medial parietal cortex and lateral temporal cortex. The effect of [18F]flutemetamol on cognition was generally weaker and less region specific.ConclusionOur findings suggest that tau PET is more sensitive than Aβ PET and measures of cortical thickness for detecting early cognitive changes in preclinical AD. Furthermore, both [18F]flortaucipir PET and cortical thickness show strong cognitive correlates at the clinical stages of AD.

Project description:Alzheimer's disease (AD), the leading cause of dementia in older adults, is a double proteinopathy characterized by amyloid-β (Aβ) and tau pathology. Despite enormous efforts that have been spent in the last decades to find effective therapies, late pharmacological interventions along the course of the disease, inaccurate clinical methodologies in the enrollment of patients, and inadequate biomarkers for evaluating drug efficacy have not allowed the development of an effective therapeutic strategy. The approaches followed so far for developing drugs or antibodies focused solely on targeting Aβ or tau protein. This paper explores the potential therapeutic capacity of an all-D-isomer synthetic peptide limited to the first six amino acids of the N-terminal sequence of the A2V-mutated Aβ, Aβ1-6A2V(D), that was developed following the observation of a clinical case that provided the background for its development. We first performed an in-depth biochemical characterization documenting the capacity of Aβ1-6A2V(D) to interfere with the aggregation and stability of tau protein. To tackle Aβ1-6A2V(D) in vivo effects against a neurological decline in genetically predisposed or acquired high AD risk mice, we tested its effects in triple transgenic animals harboring human PS1(M146 V), APP(SW), and MAPT(P301L) transgenes and aged wild-type mice exposed to experimental traumatic brain injury (TBI), a recognized risk factor for AD. We found that Aβ1-6A2V(D) treatment in TBI mice improved neurological outcomes and reduced blood markers of axonal damage. Exploiting the C. elegans model as a biosensor of amyloidogenic proteins' toxicity, we observed a rescue of locomotor defects in nematodes exposed to the brain homogenates from TBI mice treated with Aβ1-6A2V(D) compared to TBI controls. By this integrated approach, we demonstrate that Aβ1-6A2V(D) not only impedes tau aggregation but also favors its degradation by tissue proteases, confirming that this peptide interferes with both Aβ and tau aggregation propensity and proteotoxicity.

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Early active immunization with A?3-10-KLH vaccine reduces tau phosphorylation in the hippocampus and protects cognition of mice.

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Early active immunization with Aβ<sub>3-10</sub>-KLH vaccine reduces tau phosphorylation in the hippocampus and protects cognition of mice.

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