Focus on orexinergic neurons: omics study reveals glial changes and neuroinflammation in the lateral hypothalamic area as key factors driving the initial vulnerability in Alzheimer's disease

Orexinergic neurons are the earliest neuronal population to degenerate in AD, starting at Braak I. Early p-tau accumulation in the LHA, independent of major β-amyloid pathology, triggers T-cell-mediated inflammation, lysosomal dysregulation, and oxidative stress while surviving Orx<sup>N</sup> attempts compensatory gene upregulation. Overall, this highlights Orx<sup>N</sup> as a previously underrecognized target for early intervention, potentially offering both symptomatic and disease-modifying benefits. Given the availability of orexin-targeting pharmacotherapies, our data support expanded exploration of orexinergic modulation as a viable AD therapeutic strategy.

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Publication Details

Journal
Alzheimer s & Dementia
Published
2025-12-01
DOI
https://doi.org/10.1002/alz70855_107086
Primary Topic
Sleep and Wakefulness Research
Type
article
Field-Weighted Citation Impact
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article

Focus on orexinergic neurons: omics study reveals glial changes and neuroinflammation in the lateral hypothalamic area as key factors driving the initial vulnerability in Alzheimer's disease

Lea T. Grinberg, Renata Elaine Paraízo Leite, Song Hua Li, Salvatore Spina et al.
Alzheimer s & Dementia
Sleep and Wakefulness Research
article

Focus on orexinergic neurons: omics study reveals glial changes and neuroinflammation in the lateral hypothalamic area as key factors driving the initial vulnerability in Alzheimer's disease

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

Abstract

Orexinergic neurons are the earliest neuronal population to degenerate in AD, starting at Braak I. Early p-tau accumulation in the LHA, independent of major β-amyloid pathology, triggers T-cell-mediated inflammation, lysosomal dysregulation, and oxidative stress while surviving Orx<sup>N</sup> attempts compensatory gene upregulation. Overall, this highlights Orx<sup>N</sup> as a previously underrecognized target for early intervention, potentially offering both symptomatic and disease-modifying benefits. Given the availability of orexin-targeting pharmacotherapies, our data support expanded exploration of orexinergic modulation as a viable AD therapeutic strategy.

Alzheimer s & DementiaVol. 21(S1)
Universidade de São Paulo (BR), University of California, San Francisco (US), University Memory and Aging Center (US), Innovative Genomics Institute (US), University of California, Berkeley (US)
Openalex Percentile: Top 32%
Sleep and Wakefulness Research
DOIOpen Access PDFOpenAlex
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