LRP1 is a master regulator of tau uptake and spread

Abstract

Summary The spread of protein aggregates during disease progression is a common theme underlying many neurodegenerative diseases. The microtubule-associated protein tau (MAPT) plays a central role in the pathogenesis of several forms of dementia known as tauopathies, including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and chronic traumatic encephalopathy (CTE) 1 . Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity 2 . This observation and complementary experimental studies 3 , 4 have suggested that tau can spread in a prion-like manner by passing to naïve cells where it templates misfolding and aggregation. However, while tau propagation has been extensively studied, the underlying cellular mechanisms remain poorly understood. Here we show that the low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) controls tau endocytosis and subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and iPS-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule binding repeat region of tau. Furthermore, we find that downregulation of LRP1 in an in vivo mouse model of tau spread effectively reduced tau propagation between neurons. Our results identify LRP1 as a key regulator of tau spread in the brain and, thus, as a novel target for diseases of tau spread and aggregation.

Viral Delivery of Non-Mutated Human Truncated Tau to Neurons Recapitulates Key Features of Human Tauopathy in Wild-Type Mice

“…The induction of localized and targeted tau pathology is particularly useful for studying the mechanisms of tau spreading [51]. The ability to visualize infected neurons using mCherry fluorescence provides stronger basis for the interpretation of propagation of human tau compared to models that require injection of brain extract [11,50,52,53]. AAV-hSyn-htTau model is also well suited for in vivo studies of progressing tauopathy.…”

Astrocytes in Tauopathies

“…For example, HSPGs interact with members of the low-density lipoprotein receptor (LDLR) such as LRP1, to facilitate Aβ uptake and degradation by astrocytes (97,98). Knockdown of LRP1 was recently shown to block the uptake of monomeric and oligomeric tau in a human neuroglioma cell line, and partially inhibit uptake of sonicated tau fibrils (99), warranting further investigation into how astrocytic LRP1 may mediate tau uptake and spread in tauopathies.…”

Tau Conformers in FTLD-MAPT  Undergo Liquid-liquid Phase Separation and Perturb the Nuclear Envelope

“…Concerning the pathways leading to cell death, soluble oligomeric, but not monomeric nor brillar, forms of tau have long been considered to be cytotoxic due to their ability to internalize into recipient cells and recruit monomeric tau into lamentous inclusions (tau seeding activity) [64][65][66][67][68][69][70]. In addition and more recently, several lines of evidence suggest that tau uptake and aggregation are not su cient per se to cause immediate neuronal cell death [71,72].…”