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

Abstract

Tauopathies are characterized by abnormal accumulation of tau protein in neurons and glia. In Alzheimer’s disease (AD), tau aggregates in neurons, while in corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), tau also aggregates in astrocytes and oligodendrocytes. We previously demonstrated that human CBD and PSP tauopathy lysates (CBD-tau and PSP-tau) contain distinct tau strains that propagate neuronal and glial tau aggregates in nontransgenic (nonTg) mouse brain. Yet the mechanism of glial tau transmission is unknown. Here, we developed a novel mouse model to knock down tau in neurons to test for glial tau transmission. While oligodendroglial tau pathology propagated across the mouse brain in the absence of neuronal tau pathology, astrocytic tau pathology did not. Oligodendroglial tau aggregates propagated along white matter tracts independently of neuronal axons, and resulted in oligodendrocyte cell loss. Thus, glial tau pathology has significant functional consequences independent of neuronal tau pathology.

Astrocytes: News about Brain Health and Diseases

“…Tau is an important component of AD and the key factor of tauopathies. In healthy humans, tau is also present, although at lower levels [ 69 , 72 ]. Finally, AD initial symptoms, which sometimes involve astrocytes, are present in young, apparently healthy humans, destined to become patients with aging.…”

“…The possibility of exclusive neuronal origin was turned down. In a mice model where tau expression by neurons had been knocked-out, the expression in glial cells was maintained [ 69 ]. Interestingly, tau expression by both glial cells was not followed by intense spreading to other cells.…”

Experimental models of prion‐like protein propagation

“…Nevertheless, these cellular models are useful for the analysis and screening of factors, molecules and drugs that modulate seeded aggregation, and should yield new tools for modulating the aggregation and propagation of tau in the near future. The mouse models generated by inoculating abnormal tau prepared from the brains of tauopathy patients appear to reproduce well the pathological features 29,30 (Shimozawa et al, unpublished data). This is in contrast to the situation in mice injected with MSA α-synuclein.…”

Microglia in Alzheimer’s Disease in the Context of Tau Pathology

“…Once internalized, tau interacts with other tau molecules of the receptor neuron and induces their aberrant folding, thus propagating the pathology [ 116 , 119 ]. Propagation does not occur only in neurons as glia are also capable of engulfing extracellular tau [ 120 , 121 , 122 , 123 ] and therefore of contributing to tau propagation [ 124 , 125 , 126 , 127 ], although these cells have the capacity to degrade it [ 120 , 125 , 128 ] ( Figure 1 ).…”