Figure 8.

Astrocytes with TDP-43 inclusions have reduced noradrenergic signaling and dysregulated astroglial metabolism. Noradrenergic cAMP and Ca²⁺ signaling is downregulated in astrocytes expressing the ALS- and FTD-U-associated inclusion-forming C-terminal fragment of TDP-43 (TDP-43^208–414) compared to astrocytes expressing TDP-43^wt in the nucleus, possibly due to downregulation of β₂-adrenergic receptor (β₂-AR). In these cells aerobic glycolysis and lipid droplet (LD) accumulation are facilitated representing cellular stress. Moreover, monocarboxylate transporter 1 (MCT1) is downregulated in astrocytes with TDP-43 inclusions, suggesting that despite increased astroglial aerobic glycolysis astroglial L-lactate support of neurons may be reduced in ALS or FTD-U. ALS, amyotrophic lateral sclerosis; ER, endoplasmic reticulum; FTD, frontotemporal dementia with ubiquitin-positive inclusions (FTD-U); TDP-43, TAR DNA-binding protein 43.