Tau Seeding Mouse Models with Patient Brain-Derived Aggregates

Abstract

Tauopathies are a heterogeneous class of neurodegenerative diseases characterized by intracellular inclusions of aggregated tau proteins. Tau aggregates in different tauopathies have distinct structural features and can be found in different cell types. Transgenic animal models overexpressing human tau have been used for over two decades in the research of tau pathology. However, these models poorly recapitulate the heterogeneity of tauopathies found in human brains. Recent findings demonstrate that injection of purified tau aggregates from the brains of human tauopathy patients recapitulates both the structural features and cell-type specificity of the tau pathology of the donor tauopathy. These models may therefore have unique translational value in the study of functional consequences of tau pathology, tau-based diagnostics, and tau targeting therapeutics. This review provides an update of the literature relating to seeding-based tauopathy and their potential applications.

Pathological and neurophysiological outcomes of seeding human-derived tau pathology in the APP-KI NL-G-F and NL-NL mouse models of Alzheimer’s Disease

“…When interpreting these findings of this study in the context of the pathophysiological progression of AD, we suggest that several aspects and limitations should be considered. Primarily, this study involves the injection of AD-tau seeding material derived from patient brain samples, which may induce a more physiologically similar form of tau pathology compared to other methods such as transgenic methods [ 21 ]. However, it must be noted that the process of injecting seeding material is by no means physiologically representative of the disease.…”

“…This study was framed as an exploratory study aimed at characterizing and understanding the changes associated with both amyloid and tau pathology in this animal model. The tau seeding approach in this study derives tau pathology from the injection of seeding material obtained from purified human brain extracts, which may be more representative of tau pathology seen in AD [ 21 ], as opposed to transgenic mouse models of tau which derive pathology from mutations associated with frontotemporal dementia. However, it should still be noted that mice and humans still differ significantly in terms of endogenous tau properties and mice still do not fully capitulate all the nuances of tau pathology in humans.…”

“…Another recent approach to inducing tau pathology involves the injection of material that promotes the conformation of endogenous tau into pathological species, a process termed “tau seeding”. Seeding material derived from the purification of diseased human brain tissue is thought to represent the physiological processes underlying tau aggregation and spreading in AD moreso than mutations [ 21 ].…”

Dual role of brain-derived extracellular vesicles in dementia-related neurodegenerative disorders: cargo of disease spreading signals and diagnostic-therapeutic molecules

“…In addition to differences in phosphorylation sites, the seeding competency also varies among different tauopathies [ 91 ]. In recent years, many efforts have been made to study tau pathobiology [ 92 , 93 ]. The internalization of exosomal Tau seeds appears to be quite complex, given that cells internalize EVs by a variety of endocytic pathways, including clathrin-dependent and -independent pathways such as caveolin-mediated uptake, macropinocytosis, phagocytosis, and lipid raft-mediated internalization [ 94 ].…”

Towards a Mechanistic Model of Tau-Mediated Pathology in Tauopathies: What Can We Learn from Cell-Based In Vitro Assays?

“…Although in vivo models are out of the scope of the present review, we have decided to include a brief description of some of the most relevant approaches to illustrate the current trends and motivations in the “prion-like” research field. Detailed information on in vivo approaches can be found in recent reviews [ 59 , 60 , 61 ].…”