RESUMEN
Obesity, a known risk factor of Alzheimer's disease (AD), increases the activation of microglia, leading to a proinflammatory phenotype. Our previous work shows that a high fat diet (HFD) can cause neuroinflammation and cognitive decline in mice. We hypothesized that proinflammatory activation of brain microglia in obesity exacerbates AD pathology and increases the accumulation of amyloid beta (Aß) plaques. Presently, we tested cognitive function in 8-month-old male and female APP/PS1 mice fed a HFD, starting at 1.5 months of age. Locomotor activity, anxiety-like behavior, behavioral despair, and spatial memory were all assessed through behavioral tests. Microgliosis and Aß deposition were measured in multiple brain regions through immunohistochemical analysis. Our results show that a HFD decreases locomotor activity, while increasing anxiety-like behavior and behavioral despair independent of genotype. A HFD led to increased memory deficits in both sexes, with HFD-fed APP/PS1 mice performing the worst out of all groups. Immunohistochemical analysis showed increased microgliosis in mice fed a HFD. This was accompanied by an increase in Aß deposition in the HFD-fed APP/PS1 mice. Together, our results support that HFD-induced obesity exacerbates neuroinflammation and Aß deposition in a young adult AD mouse model, leading to increased memory deficits and cognitive decline in both sexes.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Masculino , Ratones , Femenino , Animales , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide , Enfermedades Neuroinflamatorias , Ratones Transgénicos , Trastornos de la Memoria/complicaciones , Disfunción Cognitiva/complicaciones , Modelos Animales de Enfermedad , Placa Amiloide/genética , Obesidad/complicaciones , Presenilina-1/genéticaRESUMEN
The microglial fatty-acid-binding protein 4-uncoupling protein 2 (FABP4-UCP2) axis is a key regulator of neuroinflammation in high-fat-diet (HFD)-fed animals, indicating a role for FABP4 in brain immune response. We hypothesized that the FABP4-UCP2 axis is involved in regulating diet-induced cognitive decline. We tested cognitive function in mice lacking microglial FABP4 (AKO mice). Fifteen-week-old male AKO and wild-type (WT) mice were maintained on 60% HFD or normal chow (NC) for 12 weeks. Body composition was measured using EchoMRI. Locomotor activity, working memory, and spatial memory were assessed using behavioral tests (open field, T-maze, and Barnes maze, respectively). Hippocampal microgliosis was assessed via immunohistochemical staining. An inflammatory cytokine panel was assayed using hippocampal tissue. Real-time RT-PCR was performed to measure microglial UCP2 mRNA expression. Our data support that loss of FABP4 prevents cognitive decline in vivo. HFD-fed WT mice exhibited impaired long- and short-term memory, in contrast with HFD-fed AKO mice. HFD-fed WT mice had an increase in hippocampal inflammatory cytokine expression (IFNγ, IL-1ß, IL-5, IL-6, KC/GRO(CXCL1), IL-10, and TNFα) and microgliosis, and decreased microglial UCP2 expression. HFD-fed AKO mice had decreased hippocampal inflammatory cytokine expression and microgliosis and increased microglial UCP2 expression compared to HFD-fed WT mice. Collectively, our work supports the idea that the FABP4-UCP2 axis represents a potential therapeutic target in preventing diet-induced cognitive decline.