Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is characterized by the accumulation of the tau protein in neurons, neurodegeneration and memory loss. However, the role of non-neuronal cells in this chain of events remains unclear. In the present study, we found accumulation of tau in hilar astrocytes of the dentate gyrus of AD patients. In mice, the overexpression of 3R tau specifically in hilar astrocytes of the dentate gyrus altered mitochondrial dynamics and function. In turn, these changes led to a reduction of adult neurogenesis, parvalbumin-expressing neurons, inhibitory synapses, and hilar gamma oscillations, which were accompanied by impaired spatial memory performances. Together, these results indicate that the loss of tau homeostasis in astrocytes of the hilus of the dentate gyrus is sufficient to induce AD-like symptoms, through the impairment of the neuronal network. These results are important for our understanding of disease mechanisms and underline the crucial role of astrocytes in hippocampal function.

Astrocytic Propagation of Tau in the Context of Alzheimer's Disease

“…Finally, APOE ε2 has been shown to increase primary tauopathy pathology when Aβ is not present (Zhao et al, 2018) and thus, effects of APOE may be dependent on the presence of Aβ pathology. Aβ is known to increase the total tau accumulation in astrocytes (Richetin et al, 2020), thus future studies are needed to parse out the effects of APOE genotype and Aβ on astrocytic tau accumulation.…”

“…While 3R and 4R tau are both found in neuronal tau pathology in the AD brain, studies describing ARTAG in AD report mainly 4R tau pathology in astrocytes (Ferrer et al, 2014;Kovacs et al, 2016;Kovacs, 2020). Most internalization studies use only 2N4R tau (Pooler et al, 2012;Holmes et al, 2013;Asai et al, 2015;Wang et al, 2017;Perea et al, 2019), which is disadvantageous because 1N isoforms are the most common in adult human brain and CSF (Barthélemy et al, 2016;Richetin et al, 2020). A recent study found 3R astrocytic tau inclusions in the hilus of the hippocampus associated with increased AD Braak stage and correlating with synaptic protein levels (Richetin et al, 2020), suggesting a relationship between astrocytic tau accumulation and synaptic degradation in AD.…”

“…Most internalization studies use only 2N4R tau (Pooler et al, 2012;Holmes et al, 2013;Asai et al, 2015;Wang et al, 2017;Perea et al, 2019), which is disadvantageous because 1N isoforms are the most common in adult human brain and CSF (Barthélemy et al, 2016;Richetin et al, 2020). A recent study found 3R astrocytic tau inclusions in the hilus of the hippocampus associated with increased AD Braak stage and correlating with synaptic protein levels (Richetin et al, 2020), suggesting a relationship between astrocytic tau accumulation and synaptic degradation in AD. Microglia internalize more 2N4R tau aggregates in vitro than do astrocytes or neurons (Asai et al, 2015), and thus microglia have come under increased scrutiny as the main cell type responsible for tau propagation.…”

“…Decreased astrocytic viability also decreases critical neuronal metabolic support, resulting in greater potential for neuron death (Prebil et al, 2011;Allen, 2014). Recent evidence also suggests that synaptic density is altered in a 1N3R tau overexpression system in astrocytes (Richetin et al, 2020) and that 1N3R overexpression also impairs mitochondrial transport and calcium homeostasis. Additionally, astrocytes overexpressing 1N3R tau in the hilus impair inhibitory neurons and cause asynchronous activity in neurons, leading to decreased spatial memory in mice (Richetin et al, 2020).…”

“…Recent evidence also suggests that synaptic density is altered in a 1N3R tau overexpression system in astrocytes (Richetin et al, 2020) and that 1N3R overexpression also impairs mitochondrial transport and calcium homeostasis. Additionally, astrocytes overexpressing 1N3R tau in the hilus impair inhibitory neurons and cause asynchronous activity in neurons, leading to decreased spatial memory in mice (Richetin et al, 2020). Taken together, this evidence and the innate phagocytic properties of astrocytes (Allen, 2014) underlines the importance of studying astrocytes in terms of tau propagation and as a potential additional driver of tau-related neurodegeneration in AD.…”