Sex-divergent effects on the NAD+-dependent deacetylase sirtuin signaling across the olfactory–entorhinal–amygdaloid axis in Alzheimer’s and Parkinson’s diseases

Abstract

Background Smell impairment is one of the earliest features in Alzheimer’s (AD) and Parkinson’s diseases (PD). Due to sex differences exist in terms of smell and olfactory structures as well as in the prevalence and manifestation of both neurological syndromes, we have applied olfactory proteomics to favor the discovery of novel sex-biased physio-pathological mechanisms and potential therapeutic targets associated with olfactory dysfunction. Methods SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) and bioinformatic workflows were applied in 57 post-mortem olfactory tracts (OT) derived from controls with no known neurological history (n = 6F/11M), AD (n = 4F/13M) and PD (n = 7F/16M) subjects. Complementary molecular analyses by Western-blotting were performed in the olfactory bulb (OB), entorhinal cortex (EC) and amygdala areas. Results 327 and 151 OT differentially expressed proteins (DEPs) were observed in AD women and AD men, respectively (35 DEPs in common). With respect to PD, 198 DEPs were identified in PD women, whereas 95 DEPs were detected in PD men (20 DEPs in common). This proteome dyshomeostasis induced a disruption in OT protein interaction networks and widespread sex-dependent pathway perturbations in a disease-specific manner, among them Sirtuin (SIRT) signaling. SIRT1, SIRT2, SIRT3 and SIRT5 protein levels unveiled a tangled expression profile across the olfactory–entorhinal–amygdaloid axis, evidencing disease-, sex- and brain structure-dependent changes in olfactory protein acetylation. Conclusions Alteration in the OT proteostasis was more severe in AD than in PD. Moreover, protein expression changes were more abundant in women than men independent of the neurological syndrome. Mechanistically, the tangled SIRT profile observed across the olfactory pathway-associated brain regions in AD and PD indicates differential NAD (+)-dependent deacetylase mechanisms between women and men. All these data shed new light on differential olfactory mechanisms across AD and PD, pointing out that the evaluation of the feasibility of emerging sirtuin-based therapies against neurodegenerative diseases should be considered with caution, including further sex dimension analyses in vivo and in clinical studies.

Proteoform Analysis of the Human Olfactory System: A Window into Neurodegenerative Diseases

“…They studied the olfactory tracts of PD and AD patients. Overall, they found that the tangled SIRT (SIRT1-5) profile observed across the olfactory pathway-associated brain regions in AD and PD indicates differential NAD (+)-dependent deacetylase mechanisms between women and men [ 43 ].…”

Downregulation of Sirtuin 1 Does Not Account for the Impaired Long-Term Potentiation in the Prefrontal Cortex of Female APPswe/PS1dE9 Mice Modelling Alzheimer’s Disease

“…Instead, to our surprise, it was SIRT1 inhibition that increased PFC-LTP in APP/PS1 female mice. These are results to be further clarified in the future, including an evaluation of potential sex-dependent differences in the action of sirtuins that was identified in some recent studies [ 79 , 80 , 81 ].…”

Neuropathological stage-dependent proteome mapping of the olfactory tract in Alzheime’s disease: From early olfactory-related omics signatures to computational repurposing of drug candidates

“…According to the Declaration of Helsinki, all assessments, post-mortem evaluations, and experimental procedures were previously approved by the Clinical Ethics Committee of Navarra Health Service (Study code: PI_2019/108). Post-mortem brain processing, extraction and fixation were performed as previously described (23). The neuropathological diagnosis was carried out according to the current neuropathological guidelines.…”

“…Protein extraction, sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS), MS/MS library generation, proteome quantitation and data analysis was performed as previously described (23). Mass-spectrometry data and search results files were deposited in the Proteome Xchange Consortium via the JPOST partner repository (https://repository.jpostdb.org) with the identifier PXD038061 for ProteomeXchange and JPST001921 for jPOST (for reviewers: https://repository.jpostdb.org/preview/1400199357636bce4231af5 Access key: 8609).…”