Neuroinflammatory responses and synaptic impairment in a Herpes simplex virus type 1 model of sporadic Alzheimer’s disease

Alzheimer's disease is a progressive neurodegenerative disorder in which neuroinflammation has emerged as a key contributor to early synaptic and cognitive dysfunction. In previous studies, we demonstrated that the spread of herpes simplex virus type 1 infection to the central nervous system and its reactivation induced by thermal stress, triggers the accumulation of Alzheimer's disease molecular hallmarks and the development of an Alzheimer's disease-like phenotype in wild-type C57BL/6 mice. In particular, two cycles of thermal stress-induced reactivation in wild-type mice induced a marked upregulation of the proinflammatory cytokine interleukin-1β, along with hippocampal synaptic and memory deficits, features reminiscent of an early stage of neurodegeneration. Notably, blocking interleukin-1β signaling with anakinra, a pharmacological interleukin-1 receptor antagonist, fully rescued all structural and functional indices of neurodegeneration, highlighting the central role of neuroinflammation in early phases of the disease. Here, we documented that, in addition to increased interleukin-1β levels, two cycles of thermal stress promoted the activation of glycogen synthase kinase 3β through phosphorylation of the tyrosine residue at position 216 (Tyr216), along with elevated phosphorylation of its direct substrates, amyloid precursor protein (APP) at threonine 668 and tau at Serine 199. To dissect the contribution of APP and tau to herpes simplex virus type 1-induced synaptic dysfunction, we employed APP-/- and Tau-/- mice. After two cycles of thermal stress, these knock-out mouse models exhibited lower increases in interleukin-1β levels and smaller synaptic deficits than infected wild-type mice, along with a distinct profile of microglial activation. To determine whether neuroinflammation remains the predominant pathological driver at later stages, we extended our analyses to herpes simplex virus type 1-infected wild-type mice subjected to six cycles of thermal stress (6TS), which recapitulate an advanced disease stage with features reminiscent of an Alzheimer's disease-like phenotype. Although interleukin- 1β levels remained persistently elevated in mice subjected to six cycles of thermal stress, anti-inflammatory treatments with either anakinra or dexamethasone failed to rescue synaptic and memory deficits, suggesting that neuroinflammation was no longer the primary pathological driver. Instead, synaptic failure correlated with a pronounced increase in glycogen synthase kinase 3β-induced APP cleavage products (e.g., amyloid-β) and hyperphosphorylated tau, indicating a stage-dependent shift in pathogenic mechanisms, whereby early neuroinflammatory responses are progressively replaced by other processes primarily mediated by glycogen synthase kinase 3β. These findings underscore the stage-specific contribution of interleukin-1β and glycogen synthase kinase 3β to herpes simplex virus type 1-induced Alzheimer's disease-like synaptic failure, highlighting the importance of a phase-specific therapeutic strategy.