Journal article
Selective reduction of KCNA4 in vulnerable glutamatergic–serotonin neurons of the dorsal raphe nucleus in Alzheimer's disease
Alzheimer's & dementia, Vol.22(5), e71317
05/2026
DOI: 10.1002/alz.71317
PMCID: PMC13162231
PMID: 42117485
Abstract
INTRODUCTION
Our previous studies demonstrate that htau mice recapitulate many of the neuropsychiatric features of early Alzheimer's disease (AD), and that the dorsal raphe nucleus (DRN) contains distinct subregions. Herein, we investigate the vulnerability of the centromedial DRN to pathologically phosphorylated tau (p-tau), a region composed predominantly of dually serotonergic/glutamatergic (5HT/glut) neurons.
METHODS
We use a battery of computational, molecular, biophysical, and behavioral techniques to assess molecular changes in the centromedial DRN across preclinical and post mortem settings.
RESULTS
The centromedial DRN contains 5HT/glut neurons that differentially express ion-channel genes in the htau mouse. This is associated with increased neuronal excitability, which may promote p-tau accumulation. At Braak II, KCNA4 is reduced in 5HT/glut neurons in AD, which are especially vulnerable to p-tau compared to 5HT-nonglut neurons.
DISCUSSION
Tau-mediated dysfunction of the DRN may be driven by changes in ion channel activity that concomitantly promote the spread of p-tau in Braak progression.
Details
- Title: Subtitle
- Selective reduction of KCNA4 in vulnerable glutamatergic–serotonin neurons of the dorsal raphe nucleus in Alzheimer's disease
- Creators
- Louis J. Kolling - University of IowaNagalakshmi Balasubramanian - Department of Neuroscience and Pharmacology University of Iowa Iowa City Iowa USA, Department of Cellular and Systems Pharmacology University of Florida Gainesville Florida USAShafa Ismail - University of IowaAlexander J. Feller - University of IowaJessica Marie Hunter Alberhasky - University of IowaRuixiang Wang - University of IowaLuke Jennings - Department of Neuroscience and Pharmacology University of Iowa Iowa City Iowa USAMarco Hefti - University of IowaCatherine Anne Marcinkiewcz - Department of Neuroscience and Pharmacology University of Iowa Iowa City Iowa USA, Department of Cellular and Systems Pharmacology University of Florida Gainesville Florida USA
- Resource Type
- Journal article
- Publication Details
- Alzheimer's & dementia, Vol.22(5), e71317
- DOI
- 10.1002/alz.71317
- PMID
- 42117485
- PMCID
- PMC13162231
- NLM abbreviation
- Alzheimers Dement
- ISSN
- 1552-5260
- eISSN
- 1552-5279
- Publisher
- Wiley; HOBOKEN
- Grant note
- National Institute on Alcohol Abuse and Alcoholism: K99 AA032034 Iowa Neuroscience Institute Research Program of Excellence (RPOE) National Institute on Aging: F32 AG084196, R01 AG070841
All authors acquired, analyzed, or interpreted data in the study. As such, we confirm that all authors approved the final version of the manuscript, agreed to be accountable for all aspects of the work, that all persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. In using the CRediT (Contributor Roles Taxonomy) guidelines: L.K. and C.M. were responsible for project conceptualization. Figures 1 and 2: data acquisition (L.K.), formal analyses (L.K.), methodology (L.K.). Figure 3: data acquisition (L.K., R.W.), formal analyses (L.K., A.F.), methodology (L.K., R.W.). Figure 4: data acquisition (L.K., N.B., S.I.), formal analyses (L.K., N.B., J.A., L.J.), methodology (L.K., N.B.). Figure 5: data acquisition (L.K., N.B., S.I.), formal analyses (L.K., S.I.), methodology (L.K., N.B.). Figures 6 and 7: data acquisition (N.B., M.H.), formal analyses (N.B., L.K., M.H.), methodology (N.B., L.K., M.H.). L.K. was responsible for writing the original draft of the manuscript; all authors contributed to reviewing and editing the manuscript. C.M. was responsible for project administration and supervision. C.M. is the guarantor of this work, and, as such, has had full access to all data and takes responsibility for its integrity and analysis. We thank Mrs. Yu Xu for excellent technical assistance and help with mouse husbandry, as well as Dr. Samantha Pierson and Mrs. Mikayla Hunter of the Iowa Neuropathology Resource Laboratory for their assistance in the procurement of post mortem tissue. This work was supported by an Iowa Neuroscience Institute Research Program of Excellence (RPOE) Award, and NIH R01 AG070841 to C.M. L.K. was supported by NIH F32 AG084196-01A1 and a Pappajohn Biomedical Institute Microfinance Grant from the University of Iowa. N.B. was supported by NIH K99AA032034. S.I. was supported by an Independent Creative Research by Undergraduates Fellowship from the University of Iowa.
- Language
- English
- Date published
- 05/2026
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9985163459902771
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