Tau Pathology in Astrocytes in Alzheimer's Disease

Astrocytes are supporting cells in the brain, and contribute to the correct function of neurons in numerous ways. It is plausible that widespread disruption of astrocyte function could lead to cognitive issues. Researchers here offer evidence to suggest that tau pathology in Alzheimer's disease extends beyond neurofibrillary tangles made up of phosphorylated tau in neurons, and also includes excessive amounts of tau in astrocytes. This appears to change astrocyte behavior in ways that negatively affect memory, but as always in Alzheimer's disease, the animal models used to assess these effects are quite artificial and may or may not be relevant to the human condition.

Tau tangles are an integral part of Alzheimer's disease (AD) pathology, appearing in the hippocampus in early stage disease and then gradually spreading throughout the brain. Their accumulation closely mirrors cognitive decline. Researchers have focused on tau's role in neuron dysfunction and death. What about other cells? Researchers looked for tau tangles in different areas of the hippocampus in tissue samples from healthy controls and from people with AD. As expected, they found them in the AD samples, but the pathology was not equally distributed; there were hot spots in certain areas, including the hilus. "The hilus is seen as a highway between the dentate gyrus and CA3 region within the hippocampus, so most researchers do not pay much attention to what happens there. It turns out to be very important."

Zooming in on the astrocytes in the hilus, researchers saw they were packed with three-repeat (3R) tau in the AD tissue samples. This isoform contributes to the 3R/4R type of neurofibrillary tangles found in Alzheimer's. The amount of 3R tau in the astrocytes correlated with tau tangles and with amyloid-β plaques in the surrounding tissue, suggesting the 3R tau accumulation may be downstream of other AD pathologies. Oddly enough, researchers found no increase in phosphorylated forms of tau in the astrocytes or any evidence of tangles in these cells. He speculated that this might be because these hilar astrocytes cells do not phosphorylate the protein as easily as neurons do, or that tau is dephosphorylated by the astrocytes.

Does this 3R tau accumulation affect the astrocytes or their surrounding neurons? To test this idea in a mouse model, researchers overproduced tau in mouse hippocampi. Researchers injected lentiviruses carrying a gene for human 3R tau into the hippocampi of 3-month-old wild-type mice. Two weeks later, they verified that the human 3R tau was expressed only in hilar astrocytes. Within these astrocytes, mitochondria languished in the cell bodies, rather than travelling to the astrocyte arms that support neurons. Mitochondrial function also suffered; the organelles replenished less often, and they produced much less ATP than usual.

Still, neurons looked normal for the most part, with no signs of neuronal death. However, neurogenesis had faltered, and the treated mice had fewer parvalbumin-positive inhibitory neurons in the dentate gyrus than controls. The number of inhibitory synapses also collapsed. Parvalbumin-producing neurons are like the pacemakers of the brain, modulating γ-frequency oscillations, which is important for working memory. Indeed, the 3R mice had weaker γ activity in the hippocampus and had trouble finding a hidden platform in a water maze. Otherwise, they seemed to behave normally. Taken together, the results suggested that accumulation of tau in hilar astrocytes compromised the function of hippocampal inhibitory neurons.

Link: https://www.alzforum.org/news/research-news/does-astrocyte-tau-cause-dementia

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