Human tau-overexpressing mice recapitulate brainstem involvement and neuropsychiatric features of early Alzheimer's disease

Kanza M Khan; Nagalakshmi Balasubramanian; Gabriel Gaudencio; Ruixiang Wang; Govindhasamy Pushpavathi Selvakumar; Louis Kolling; Samantha Pierson; Satya M Tadinada; Ted Abel; Marco Hefti; Catherine A Marcinkiewcz

doi:10.1186/s40478-023-01546-5

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Human tau-overexpressing mice recapitulate brainstem involvement and neuropsychiatric features of early Alzheimer's disease

Journal article

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Human tau-overexpressing mice recapitulate brainstem involvement and neuropsychiatric features of early Alzheimer's disease

Kanza M Khan, Nagalakshmi Balasubramanian, Gabriel Gaudencio, Ruixiang Wang, Govindhasamy Pushpavathi Selvakumar, Louis Kolling, Samantha Pierson, Satya M Tadinada, Ted Abel, Marco Hefti, …

Acta neuropathologica communications, Vol.11(1), 57

04/03/2023

DOI: 10.1186/s40478-023-01546-5

PMCID: PMC10069039

PMID: 37009893

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Abstract

Alzheimer's disease (AD) poses an ever-increasing public health concern as the population ages, affecting more than 6 million Americans. AD patients present with mood and sleep changes in the prodromal stages that may be partly driven by loss of monoaminergic neurons in the brainstem, but a causal relationship has not been firmly established. This is due in part to a dearth of animal models that recapitulate early AD neuropathology and symptoms. The goal of the present study was to evaluate depressive and anxiety-like behaviors in a mouse model of AD that overexpresses human wild-type tau (htau) prior to the onset of cognitive impairments and assess these behavior changes in relationship to tau pathology, neuroinflammation, and monoaminergic dysregulation in the dorsal raphe nucleus (DRN) and locus coeruleus (LC). We observed depressive-like behaviors at 4 months in both sexes and hyperlocomotion in male htau mice. Deficits in social interaction persisted at 6 months and were accompanied by an increase in anxiety-like behavior in males. The behavioral changes at 4 months coincided with a lower density of serotonergic (5-HT) neurons, downregulation of 5-HT markers, reduced excitability of 5-HT neurons, and hyperphosphorylated tau in the DRN. Inflammatory markers were also upregulated in the DRN along with protein kinases and transglutaminase 2, which may promote tau phosphorylation and aggregation. Loss of 5-HT innervation to the entorhinal cortex and dentate gyrus of the hippocampus was also observed and may have contributed to depressive-like behaviors. There was also reduced expression of noradrenergic markers in the LC along with elevated phospho-tau expression, but this did not translate to a functional change in neuronal excitability. In total, these results suggest that tau pathology in brainstem monoaminergic nuclei and the resulting loss of serotonergic and/or noradrenergic drive may underpin depressive- and anxiety-like behaviors in the early stages of AD.

Alzheimer Disease - pathology

Animals

Disease Models, Animal

Dorsal Raphe Nucleus - metabolism

Female

Humans

Locus Coeruleus - metabolism

Male

Mice

Norepinephrine - metabolism

Serotonin - metabolism

tau Proteins - genetics

tau Proteins - metabolism

Details

Title: Subtitle: Human tau-overexpressing mice recapitulate brainstem involvement and neuropsychiatric features of early Alzheimer's disease
Creators: Kanza M Khan - Psychological Sciences Department, Daemen University, Amherst, NY, 14226, USA
Nagalakshmi Balasubramanian - University of Iowa
Gabriel Gaudencio - Department of Neuroscience and Pharmacology, University of Iowa, 2-430 Bowen Science Building, Iowa City, IA, 52242, USA
Ruixiang Wang - University of Iowa
Govindhasamy Pushpavathi Selvakumar - Department of Neuroscience and Pharmacology, University of Iowa, 2-430 Bowen Science Building, Iowa City, IA, 52242, USA
Louis Kolling - University of Iowa
Samantha Pierson - Department of Neuroscience and Pharmacology, University of Iowa, 2-430 Bowen Science Building, Iowa City, IA, 52242, USA
Satya M Tadinada - University of Iowa
Ted Abel - University of Iowa
Marco Hefti - Department of Pathology, University of Iowa, Iowa City, IA, 52242, USA
Catherine A Marcinkiewcz - Department of Neuroscience and Pharmacology, University of Iowa, 2-430 Bowen Science Building, Iowa City, IA, 52242, USA. catherine-marcinkiewcz@uiowa.edu
Resource Type: Journal article
Publication Details: Acta neuropathologica communications, Vol.11(1), 57
DOI: 10.1186/s40478-023-01546-5
PMID: 37009893
PMCID: PMC10069039
NLM abbreviation: Acta Neuropathol Commun
ISSN: 2051-5960
eISSN: 2051-5960
Grant note: R01 AG070841 / NIA NIH HHS T32 GM067795 / NIGMS NIH HHS R00 AA024215 / NIAAA NIH HHS T32 NS045549 / NINDS NIH HHS T32 DK112751 / NIDDK NIH HHS K99 AA024215 / NIAAA NIH HHS R01 AA028931 / NIAAA NIH HHS
Language: English
Date published: 04/03/2023
Academic Unit: Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
Record Identifier: 9984385055202771

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