Neuropathological stage‐dependent proteome mapping of the olfactory tract in Alzheimer's disease: From early olfactory‐related omics signatures to computational repurposing of drug candidates

• Published in: Brain pathology (Zurich, Switzerland) Vol. 34; no. 4; pp. e13252 - n/a
• Main Authors: Cartas‐Cejudo, Paz, Cortés, Adriana, Lachén‐Montes, Mercedes, Anaya‐Cubero, Elena, Puerta, Elena, Solas, Maite, Fernández‐Irigoyen, Joaquín, Santamaría, Enrique
• Format: Journal Article
• Language: English
• Published: Switzerland John Wiley & Sons, Inc 01.07.2024; John Wiley and Sons Inc
• Subjects: 1-Phosphatidylinositol 3-kinase; Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid precursor protein; Aurora kinase; Aurora Kinases - antagonists & inhibitors; Cell Line, Tumor; Computational Chemistry; Computational neuroscience; Connectivity Map; Dementia disorders; Drug development; Drug Repositioning - methods; drug repurposing; Enzyme inhibitors; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; Female; Gene expression; Gene sequencing; Glycogen; Glycogen synthase kinase 3; Glycogens; Growth factors; Humans; Hydrogen peroxide; Insulin-like growth factors; Kinases; Microtubules; Middle Aged; Morpholines - pharmacology; Neural networks; Neurodegenerative diseases; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neurotoxicity; Olfaction; Olfactory Bulb - metabolism; Olfactory Bulb - pathology; olfactory tract; Pretreatment; Protein kinase C; Protein Kinase Inhibitors - pharmacology; Proteome; Proteomes; proteomics; Purines - pharmacology; Quinazolines - pharmacology; Signatures; Substrates; Tau protein; Tyrphostins - pharmacology; β-Amyloid; drug repurposing; proteomics; olfactory tract; Connectivity Map
• ISSN: 1015-6305; 1750-3639; 1750-3639
• DOI: 10.1111/bpa.13252

Alzheimer's disease (AD) is the most common form of dementia, characterized by an early olfactory dysfunction, progressive memory loss, and behavioral deterioration. Albeit substantial progress has been made in characterizing AD‐associated molecular and cellular events, there is an unmet clinical need for new therapies. In this study, olfactory tract proteotyping performed in controls and AD subjects (n = 17/group) showed a Braak stage‐dependent proteostatic impairment accompanied by the progressive modulation of amyloid precursor protein and tau functional interactomes. To implement a computational repurposing of drug candidates with the capacity to reverse early AD‐related olfactory omics signatures (OMSs), we generated a consensual OMSs database compiling differential omics datasets obtained by mass‐spectrometry or RNA‐sequencing derived from initial AD across the olfactory axis. Using the Connectivity Map‐based drug repurposing approach, PKC, EGFR, Aurora kinase, Glycogen synthase kinase, and CDK inhibitors were the top pharmacologic classes capable to restore multiple OMSs, whereas compounds with targeted activity to inhibit PI3K, Insulin‐like growth factor 1 (IGF‐1), microtubules, and Polo‐like kinase (PLK) represented a family of drugs with detrimental potential to induce olfactory AD‐associated gene expression changes. To validate the potential therapeutic effects of the proposed drugs, in vitro assays were performed. These validation experiments revealed that pretreatment of human neuron‐like SH‐SY5Y cells with the EGFR inhibitor AG‐1478 showed a neuroprotective effect against hydrogen peroxide‐induced damage while the pretreatment with the Aurora kinase inhibitor Reversine reduced amyloid‐beta (Aβ)‐induced neurotoxicity. Taken together, our data pointed out that OMSs may be useful as substrates for drug repurposing to propose novel neuroprotective treatments against AD. Drug repositioning used to reverse olfactory omics signatures to find new potential therapeutic options against Alzheimer'disease.