In response to CFS in Dbh+ mice, we observed AEP-tau within nuclei, somata, and dendrites of CA1 and EC neurons, supporting the concept that CFS results in metabolic stress in CA1 and EC pyramidal neurons, which in turn results in tau mislocalization and increased vulnerability to cleavage by AEP. Here, MAPT is linked to myalgic encephalomeyelitis/chronic fatigue syndrome.