p-Tau immunotherapy reduces soluble and insoluble tau in aged 3xTg-AD mice - PubMed (original) (raw)

p-Tau immunotherapy reduces soluble and insoluble tau in aged 3xTg-AD mice

Ken C Walls et al. Neurosci Lett. 2014.

Abstract

Alzheimer's disease (AD) is a proteinopathy characterized by the accumulation of β-amyloid (Aβ) and tau. To date, clinical trials indicate that Aβ immunotherapy does not improve cognition. Consequently, it is critical to modulate other aspects of AD pathology. As such, tau represents an excellent target, as its accumulation better correlates with cognitive impairment. To determine the effectiveness of targeting pathological tau, with Aβ pathology present, we administered a single injection of AT8, or control antibody, into the hippocampus of aged 3xTg-AD mice. Extensive data indicates that phosphorylated Ser(202) and Thr(205) sites of tau (corresponding to the AT8 epitope) represent a pathologically relevant target for AD. We report that immunization with AT8 reduced somatodendritic tau load, p-tau immunoreactivity, and silver stained positive neurons, without affecting Aβ pathology. We also discovered that tau pathology soon reemerges post-injection, possibly due to persistent Aβ pathology. These studies provide evidence that targeting p-tau may represent an effective treatment strategy: potentially in conjunction with Aβ immunotherapy.

Keywords: Alzheimer's disease; Beta-amyloid; Immunotherapy; Neurofibrillary tangles; Phosphorylated tau; Tau.

Copyright © 2014. Published by Elsevier Ireland Ltd.

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Figures

Fig. 1

Fig. 1

Immunization with the AT8-antibody reduces somatodendritic tau immunoreactivity. Total tau levels were quantified in 15–18-month-old 3xTg-AD mice following a single intrahippocampal injection with AT8 or a control IgG. Mice were sacrificed at post injection day 7, 14, 21, or 28. (A) Immunohistochemical analysis reveled sharp decreases in total tau (HT7) levels after immunization with AT8 at days 7 and 14, but not days 21 and 28. (B) Statistical analysis of the change in total tau between AT8 treated and control IgG treated hippocampal sides (_t_-test, ***P < 0.0001, **P < 0.008, N = 3–7). Scale bar equals 500 µm.

Fig. 2

Fig. 2

Tau immunization does not affect Aβ pathology. Total Aβ levels were also quantified following AT8 injection at post injection day 7, 14, 21, or 28. (A) In contrast to what was observed for tau, immunohistochemical analysis against Aβ (6E10) detected no differences between AT8 and control IgG treated hippocampi at either time point analyzed. (B) Statistical analysis of the change in total Aβ load between AT8 treated and control IgG treated hippocampal sides (N = 3–7). Scale bar equals 500 µm.

Fig. 3

Fig. 3

Immunization with the 4G8-antibody reduces intra- and extracellular Aβ. In addition to treatment with AT8, a small cohort of 15–18-month-old 3xTg-AD mice was treated with either the anti-Aβ antibody 4G8 or a control IgG. (A) Staining for total Aβ load (6E10) revealed that 4G8 injection drastically reduced intra- and extracellular Aβ at days 7 and 14. (B) Statistical analysis of Aβ immunization in 4G8 vs. control IgG hippocampal sections (_t_-test, ***P < 0.0003, **P < 0.0057, N = 3–7). Scale bar equals 500 µm.

Fig. 4

Fig. 4

Targeting p-tau via immunization significantly reduces early AT8 immunoreactivity. The phosphorylated residues of tau that make up the AT8 epitope also represent some of the earliest modifications observed in tau pathogenesis. (A) Staining for phosphorylated residues Ser199 and Thr202 (AT8) show a large decreased in reactive at 7 days post-injection. (B) Statistical analysis of AT8 immunoreactivity, at post injection day 7, reveals a significant decrease in AT8 treated vs. control IgG treated sections (_t_-test, ***P < 0.0001, N = 7). Scale bar equals 250 µm.

Fig. 5

Fig. 5

3xTg-AD mice immunized with AT8 have reduced Gallyas positive neurons one week post-injection. (A) Using the Gallyas silver stain method, we observed fewer Gallyas positive neurons in hemispheres treated with AT8 at 7 days. (B) Statistical analysis of Gallyas staining after AT8 treatment (_t_-test, ***P < 0.0001, N = 7). Scale bar equals 250 µm.

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