The use of mouse models to study cell-to-cell transmission of pathological tau

Abstract

Tau protein aggregates are found in a variety of neurodegenerative diseases known as tauopathies. Emerging evidence shows tau can propagate from cell-to-cell by seeding endogenous tau to aggregate. Studies in tau transgenic mice showed intracerebrally injecting misfolded tau seeds initiates and transmits tau pathology across the mouse brain. However, transgenic mice that overexpress human tau with disease-associated mutations do not fully recapitulate sporadic tauopathies. Here, we present our method for developing a sporadic tauopathy model using pathological tau extracted from human Alzheimer’s disease (AD) brains. We describe a novel method for sequentially extracting tau pathologies from human AD brain in high yield and purity. We then describe how to intracerebrally inject this extract into a nontransgenic mouse brain and analyze the transmission of tau pathology. This novel sporadic tauopathy model can be used to study the transmission of tau aggregates and test new tau-directed therapies.

Human tau pathology transmits glial tau aggregates in the absence of neuronal tau

“…All cases were diagnosed based on accepted neuropathology criteria (Irwin et al, 2015; Montine et al, 2016). Purification of pathological, insoluble tau from the frontal cortex of these cases was performed as previously described (Guo et al, 2016; Narasimhan and Lee, 2017).…”

“…The final purified supernatants contained insoluble, pathological tau, and are identified as AD-tau, CBD-tau, and PSP-tau in subsequent experiments. The different fractions from each purification were analyzed by Western blotting and sandwich ELISA for tau as previously described (Guo et al, 2016; Narasimhan and Lee, 2017). The sandwich ELISA and Western blotting for tau in the final supernatant were used for estimates of tau concentration (see Table S1).…”

“…Stereotaxic surgery on nonTg mice was performed as previously described (Narasimhan et al, 2017; Narasimhan and Lee, 2017). The mice were aseptically inoculated with human brain extracts in the dorsal hippocampus and overlying cortex of one hemisphere (bregma: −2.5 mm; lateral: +2 mm; depth: −2.4 mm and −1.4 mm from the skull).…”

“…CBD-tau–injected TauKDn cre;fl/fl mice or Tau fl/fl mice were sacrificed, and cardiac perfusion was performed at 3 mo p.i. as previously described (Narasimhan and Lee, 2017). Mouse brains were fixed in either 2% paraformaldehyde + 0.05% glutaraldehyde in 0.1 M cacodylate buffer (pH 7.4) or periodate-lysine-paraformaldehyde buffer (2% paraformaldehyde + 0.075 M lysine + 0.01 M Na-m-periodate in 0.037 M NaH 2 PO4 buffer, pH 7.0) for 2 h, and then were sectioned on the vibratome at 70 µm sections.…”

Peripheral inflammation promotes brain tau transmission via disrupting blood–brain barrier

“…Tau protein, without clear secondary or tertiary structure, is prone to misfolding to form fibrous aggregates under pathological conditions. Studies have shown that pathological tau protein aggregation can spread in different brain regions, which is closely associated with cognitive impairments in AD [4,5]. In the early stage of AD, tau protein first appears in the entorhinal cortex (EC) and then spreads to the hippocampus [6,7].…”