Translational studies on Alzheimer’s disease : a focus on cholesterol metabolism, thioredoxin-80 and microglia function

Abstract

Disturbances in cholesterol metabolism and inflammatory processes may have a negative impact on brain health. These two aspects are considered to be signs of early changes in Alzheimer’s Disease (AD). However, clear molecular links between them as well as mechanisms for their early detection are missing in the context of neurodegeneration and AD. 27-hydroxycholesterol (27-OHC), a cholesterol metabolite and Thioredoxin-80 (Trx80), an antioxidant-derived peptide with immune modulatory properties have been shown to be altered in the brain of AD patients. Thus, this thesis aims to investigate the involvement of 27-OHC and Trx80 in AD.

In Papers I, II and IV, we investigated the effect of alterations in cholesterol metabolism and inflammation during aging in relation to cognition and different risk factors for AD. In Paper I we measured 27-OHC levels in serum samples of older adults undergoing a two-year multimodal lifestyle/vascular intervention. At baseline, higher 27-OHC correlated with lower memory scores, total gray matter and hippocampal volume. After the two-year intervention trial, 27-OHC levels decreased in the intervention group. This reduction was positively correlated with improved memory scores among the intervention group. In Paper II, Trx80 was measured in serum samples in the same individuals as the previous study and in patients with varying degrees of dementia. We found that serum Trx80 levels were increased in AD cases and were positively correlated with older age and associated with the presence of ApoE4 genotype, indicating that serum Trx80 levels are sensitive to two main risk factors of AD.

Previous studies in our lab showed that Trx80 can prevent amyloid-beta (Aβ) aggregation and inhibit Aβ toxic effects in cell cultures. In view of these findings, in Papers III and IV we investigated whether Trx80 could have a similar effect on Aβ in in vivo models of amyloid pathology by inducing specific activation responses in brain cells. In Paper III, we further explored the anti-amyloidogenic properties of Trx80 in vivo in Drosophila melanogaster models. Trx80 expression in Drosophila brain prevented Aβ42 accumulation and rescued the lifespan reduction and locomotor impairments observed in Aβ42-expressing flies by enhancing the autophagy-lysosomal pathway. In Paper IV, we aimed to further clarify the biological function of Trx80 and its regulation in the brain both under healthy and AD-relevant pathological conditions. We show that neurons are the main source of Trx80 in the brain, and that its levels increase during normal aging, oxidative-stress conditions and in a mouse model of amyloid pathology. RNA-sequencing analysis revealed that Trx80 induces microglia activation into a phenotype compatible with type-I interferon response microglia.

These findings highlight the involvement of cholesterol metabolism and inflammation, related to changes in 27-OHC and Trx80, in AD pathogenesis. 27- OHC and Trx80 should be further investigated not only as potential biomarkers for AD, but also as part of therapeutic and preventive strategies in AD.