Brain region- and sex-specific alterations in mitochondrial function and NF-κB signaling in the TgCRND8 mouse model of Alzheimer's disease

Alzheimer's disease (AD) is the most common late onset neurodegenerative disorder with indications that women are disproportionately affected. Mitochondrial dysfunction has been one of the most discussed hypotheses associated with the early onset and progression of AD, and it has been attributed to intraneuronal accumulation of amyloid β (Aβ). It was suggested that one of the possible mediators for Aβ-impaired mitochondrial function is the nuclear factor kappa B (NF-κB) signaling pathway. NF-κB plays important roles in brain inflammation and antioxidant defense, as well as in the regulation of mitochondrial function, and studies have confirmed altered NF-κB signaling in AD brain. In this study, we looked for sex-based differences in impaired bioenergetic processes and NF-κB signaling in the AD-like brain using transgenic (Tg) CRND8 mice that express excessive brain Aβ, but without tau pathology. Our results show that mitochondrial dysfunction is not uniform in affected brain regions. We observed increased basal and coupled respiration in the hippocampus of TgCRND8 females only, along with a decreased Complex II-dependent respiratory activity. Cortical mitochondria from TgCRND8 mice have reduced uncoupled respiration capacity, regardless of sex. The pattern of changes in NF-κB signaling was the same in both brain structures, but was sex specific. Whereas in females there was an increase in all three subunits of NF-κB, in males we observed increase in p65 and p105, but no changes in p50 levels. These results demonstrate that mitochondrial function and inflammatory signaling in the AD-like brain is region- and sex-specific, which is an important consideration for therapeutic strategies.