Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC’s afferent and efferent connections

Abstract

Filamentous tau inclusions are hallmarks of Alzheimer’s disease (AD) and other neurodegenerative tauopathies. An increasing number of studies implicate the cell-to-cell propagation of tau pathology in the progression of tauopathies. We recently showed [25] that inoculation of preformed synthetic tau fibrils (tau PFFs) into the hippocampus of young transgenic (Tg) mice (PS19) overexpressing human P301S mutant tau induced robust tau pathology in anatomically connected brain regions including the locus coeruleus (LC). Since Braak and colleagues hypothesized that the LC is the first brain structure to develop tau lesions and since LC has widespread connections throughout the CNS, LC neurons could be the critical initiators of the stereotypical spreading of tau pathology through connectome-dependent transmission of pathological tau in AD. Here, we report that injections of tau PFFs into the LC of PS19 mice induced propagation of tau pathology to major afferents and efferents of the LC. Notably, tau pathology propagated along LC efferent projections was localized not only to axon terminals but also to neuronal perikarya, suggesting transneuronal transfer of templated tau pathology to neurons receiving LC projections. Further, brainstem neurons giving rise to major LC afferents also developed perikaryal tau pathology. Surprisingly, while tangle bearing neurons degenerated in the LC ipsilateral to the injection site starting 6 months post-injection, no neuron loss was seen in the contralateral LC wherein tangle bearing neurons gradually cleared tau pathology by 6–12 months post-injection. However, the spreading pattern of tau pathology observed in our LC-injected mice is different from that in AD brains since hippocampus and entorhinal cortex, which are affected in early stages of AD, were largely spared of tau inclusions in our model. Thus, while our study tested critical aspects of the Braak hypothesis of tau pathology spread, this novel mouse model provides unique opportunities to elucidate mechanisms underlying the selective vulnerability of neurons to acquire tau pathology and succumb to or resist tau-mediated neurodegeneration.

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

“…Measuring the kinetics of PrP Sc and MSA propagation following intracerebral injection into Tg mice has been important in discerning the underlying biology of these prions. However, although intracerebral injection of tau fibrils into Tg mice expressing tau transgenes resulted in tau neuropathology, such experiments were inconclusive with respect to assessing the kinetics and accumulation of tau prions (40)(41)(42)(43)(44). Instead, measurements made from cells expressing the tau-YFP fusion proteins (31,32,45) have been more informative.…”

Investigating in vivo the principles governing the spread of tau phosphorylation and amyloid-beta excitotoxicity

“…This hypothesis dictates that templatemisfolding of hyperphosphorylated tau is able to seed further protein aggregation, which can be transmitted along anatomically connected neurons, leading to a systematic and chronological progression of disease pathology. Comprehensive in vivo studies have shown that injection both of whole brain lysates and isolated recombinant tau aggregates can accelerate tau pathology at both the injection site and in neighbouring, anatomically connected brain regions when done in presymptomatic tau transgenic mouse models [143,144,147,148]. Although this data convincingly supports the concept that pathological forms of tau can seed further aggregation of mature structural confirmation, it does not address how the initiation of primary aggregation events occur and how this triggers further dissemination throughout the neural system.…”

“…Tau has proven to be integral to the seeding observed in this model as prior immuno-depletion of tau decreases the seeding efficacy [144][145][146]; however, clarification of the specific species of tau that is responsible is an ongoing field of research. While in vitro aggregated forms of recombinant tau, including short fibrils from full-length P301S mutations and truncations of the microtubule-binding region have been shown to seed in presymptomatic tau mutant mice (both P301L and P301S), the precise composition and conformation of these artificial tau fibrils is not known [147][148][149]. Their confirmation may be influenced by both the tags used for their immunohistological visualisation and by pre-injection sonication that can induce β-pleated sheet structures and promote aggregation of tau [150,151].…”

“…Although this model presents and interesting platform to investigate tau properties in the absence of human transgenes, it is difficult to identify the specific tau species responsible for the observed effects. To date investigation into the species involved in tau spreading has focused on tau seeds which are freely available from brain lysate or recombinant protein isolations [143,144,[147][148][149]. The ability of these species to spread and seed has been assessed in vitro in microfluidic chambers and FRET biosensor cells and in vivo predominantly in the ALZ17 human tau transgenic mice [144,145,165].…”

“…While there has been indication that endogenous tau is not required to initiate tau pathology, recent data has demonstrated that a tau knock-out background does not affect the ability of tau to propagate but can reduce the pathological alterations induced by the 'seed' [140]. Furthermore, injection of synthetic tau fibrils alone are able to induce the propogation of tau pathology [147,148] . However, the use of mature fibrillar tau seeds in previous seeding studies supersedes the initial seeding event causal of the primary aggregation events in the human disease state.…”