Basic Science and Pathogenesis

We recently demonstrated that reactivation of Herpes Simplex Virus type 1 (HSV-1) in the mouse brain, triggered by thermal stress (TS), induces an Alzheimer's disease (AD)-like phenotype characterized by synaptic and memory deficits, elevated interleukin-1β (IL-1β) levels, and the accumulation of amyloid-β (Aβ) and phosphorylated Tau (pTau) proteins. Treatment with the IL-1 receptor blocker anakinra reversed the structural and functional markers of neurodegeneration observed after 2TS. Here, we investigated the interplay among IL-1β, Aβ, and Tau in driving synaptic dysfunction in infected mice.

Following HSV-1 infection and 2TS-induced viral reactivations, molecular, electrophysiological, and behavioral analyses were conducted on C57BL/6 wild-type (WT) and transgenic mice deficient in either Aβ (APP^-/-) or pTau (Tau^-/-) production.

After 2TS, HSV-1-infected Tau^-/- and APP^-/- mice exhibited higher IL-1β mRNA levels than mock-infected mice (1.6- and 1.4-fold increases, respectively, p <0.05). However, IL-1β levels were significantly lower than those observed in HSV-1-infected WT mice (-32% and -43%, respectively, p <0.05). The decreased concentration of IL-1β in HSV-1-infected transgenic mice correlated with reduced microglial activation. In particular, the upregulation of the M1 microglial marker CD86 was significantly lower in HSV-1-infected Tau^-/- and APP^-/- mice (+63% and +64% vs mock-infected mice, respectively) compared to the much greater increase observed in WT mice (+197%). Accordingly, transgenic mice showed milder synaptic deficits than WT mice. Specifically, hippocampal long-term potentiation (LTP) in HSV-1-infected vs mock-infected mice was: 73.7±6.7% vs 98.6±10.1% in Tau^-/-, 69.5±5.6% vs 94.6±6.4% in APP^-/-, and 47.3±6.4% vs 98.0±12.4% in WT mice. HSV-1-infected mice also exhibited memory impairments, as assessed by the novel object recognition test. Specifically, the preference index was: 50.7±1.3% vs 62.0±1.6% in Tau^-/-, 55.7±2.2% vs 62.5±2.1% in APP^-/-, and 51.6±2.1% vs 65.2±1.6% in WT mice (p <0.05 for all groups).

Our findings suggest that IL-1β-mediated neuroinflammation plays a pivotal role in driving synaptic dysfunction during the early stages of this mouse model of AD. The lower IL-1β levels and reduced synaptic deficits observed in mice lacking either Aβ or pTau indicate that these key AD hallmarks contribute to IL-1β accumulation, thereby triggering a vicious circle in the pathophysiology of synaptic dysfunction in AD.