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Deciphering the molecular signature of selective neuronal vulnerability in the wake‐promoting lateral hypothalamic area in Alzheimer’s disease: A digital multiplexed gene expression study across Braak stages

2023; Wiley; Volume: 19; Issue: S12 Linguagem: Inglês

10.1002/alz.079466

1552-5279

Abhijit Satpati, Felipe Luiz Pereira, A. A. Soloviev, Mihovil Mladinov, Renata Elaine Paraízo Leite, Cláudia Kimie Suemoto, Roberta Diehl Rodriguez, Vítor Ribeiro Paes, Christine M. Walsh, Salvatore Spina, William W. Seeley, Carlos Augusto Pasquallucci, Wilson Jacob Filho, Thomas C. Neylan, Lea T. Grinberg,

Circadian rhythm and melatonin

Abstract Background Sleep/wake disturbance is a common and debilitating symptom of Alzheimer’s disease (AD) that precedes cognitive loss. The lateral hypothalamic area (LHA) is critical in orchestrating the sleep/wake cycle through the neuropeptide orexin and melanin‐concentrating hormone. We previously demonstrated that LHA neurons accumulate AD‐tau from Braak stage (BB) 0 and losses ∼72% of neurons by BB6. Little is known about the molecular changes underlying LHA vulnerability during AD progression. We investigated RNA expression changes in LHA across Braak stages to close this gap. Method We dissected LHA from 30um‐thick sections of the brain from healthy control (HC) and subjects at progressive AD stages and extracted RNA using conventional techniques. We ran RNA transcriptomic assay using customized and neuropathology nCounter ® (Nanostring) panels. The Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when log2 fold‐change was > = |1| and the p‐value was <0.05. Result We found an upregulation of HCRTR1, LDHC, NKX6, and SLC11A1 from early stages (BB2‐3), whereas HCRTR2 RNA levels remained stable. Circadian gene PER2 was downregulated from the intermediate stages (BB4). Gene Ontology analyses detected dysregulation of neuropeptide‐ligand interaction pathways from early AD. Linoleic acid metabolism, fat digestion and absorption, and immune pathways became dysregulated at intermediate stages, while glycolysis and gluconeogenesis pathways were in late stages (BB5‐6). Of note, it is critical to consider that the massive LHA neuronal loss during AD progression may confound the interpretation of changes in late stages because of the few remaining neurons. Conclusion nCounter ® is suitable for identifying transcriptome changes in LHA, even at early AD stages. Molecular profiling of LHA across the Braak stage revealed that the earliest changes are associated with an imbalance in neurotransmitter receptors, while the decline in metabolism and increased inflammation marked the intermediate stage. The late‐stage AD is characterized by hypoglycemia and energy deficit. Notably, discrepancies in receptor behavior can inform more effective symptomatic treatment for sleep dysfunction in AD.