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English: Figure 3Schematic Representation of the Mechanisms Underlying Acute [Herpes Simplex Encephalitis (HSE)] and Long-term Central Nervous System (CNS) Damage Caused by Herpes Simplex Virus-1 (HSV-1).Upper panel: HSE. Toll-like receptors (TLRs) on astrocytes (pink) and microglia (green) recognize HSV-1 pathogen-associated molecular patterns (PAMPs), to which they bind, inducing the production of specific cytokines and chemokines through activation of intracellular signaling pathways mediated by NF-κB or interferon (IFN) regulatory factors (IRFs). Type I IFN is also induced upon recognition of viral nucleotides by the microglial cGAS–STING axis. PAMP recognition also induces the expression of the enzyme inducible nitric oxide (NO) synthase (iNOS) and production of reactive oxygen species (ROS) in glial cells, resulting in massive inflammation. Lower panel: long-term damage caused by recurrent HSV-1 infection. Neuronal HSV-1 infection triggers intracellular Ca2+ signaling and induces glycogen synthase kinase 3 (GSK3) activation and consequent production of Aβ peptides (Aβs) and several amyloid precursor protein (APP) fragments, including APP intracellular domain (AICD). AICD may act as a transcriptional regulator at the promoter of GSK3, promoting expression and activation of GSK3, which is also involved in Tau hyperphosphorylation. Aβs accumulate both inside and outside neurons where they form plaques. Recognition of Aβ oligomers by TLR2 on the surface of glial cells induces localized neuroinflammation through the release of proinflammatory cytokines, ROS, and NOS, and the consequent decrease in Aβ phagocytosis.