Deciphering Early and Progressive Molecular Signatures in Alzheimer's Disease through Integrated Longitudinal Proteomic and Pathway Analysis in a Rodent Model

• Published in: International journal of molecular sciences Vol. 25; no. 12; p. 6469
• Main Authors: Yadikar, Hamad, Ansari, Mubeen A, Abu-Farha, Mohamed, Joseph, Shibu, Thomas, Betty T, Al-Mulla, Fahd
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.06.2024; MDPI
• Subjects: Advertising executives; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Alzheimer’s disease proteomics; Animals; Biomarkers; Biomarkers - metabolism; Brain research; Data mining; Disease; Disease Models, Animal; Disease Progression; Diseases; Glucose; Huntingtons disease; Hypotheses; Insulin resistance; intracerebroventricular streptozotocin; Kuwait; Machine learning; Male; Metabolism; Mice; neurodegenerative biomarkers; Pathogenesis; Pathology; pathway dysregulation; Peptides; Pharmacogenetics; Protein expression; Proteins; Proteome - metabolism; Proteomics - methods; Scientific equipment and supplies industry; Signal Transduction; Target marketing; temporal expression profiling; United States; Kuwait; United States; Alzheimer’s disease proteomics; pathway dysregulation; intracerebroventricular streptozotocin; neurodegenerative biomarkers; temporal expression profiling
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25126469

Alzheimer's disease (AD), the leading cause of dementia worldwide, remains a challenge due to its complex origin and degenerative character. The need for accurate biomarkers and treatment targets hinders early identification and intervention. To fill this gap, we used a novel longitudinal proteome methodology to examine the temporal development of molecular alterations in the cortex of an intracerebroventricular streptozotocin (ICV-STZ)-induced AD mouse model for disease initiation and progression at one, three-, and six-weeks post-treatment. Week 1 revealed metabolic protein downregulation, such as Aldoa and Pgk1. Week 3 showed increased Synapsin-1, and week 6 showed cytoskeletal protein alterations like Vimentin. The biological pathways, upstream regulators, and functional effects of proteome alterations were dissected using advanced bioinformatics methods, including Ingenuity Pathway Analysis (IPA) and machine learning algorithms. We identified Mitochondrial Dysfunction, Synaptic Vesicle Pathway, and Neuroinflammation Signaling as disease-causing pathways. Huntington's Disease Signaling and Synaptogenesis Signaling were stimulated while Glutamate Receptor and Calcium Signaling were repressed. IPA also found molecular connections between PPARGC1B and AGT, which are involved in myelination and possible neoplastic processes, and MTOR and AR, which imply mechanistic involvements beyond neurodegeneration. These results help us comprehend AD's molecular foundation and demonstrate the promise of focused proteomic techniques to uncover new biomarkers and therapeutic targets for AD, enabling personalized medicine.