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Locus coeruleus vulnerability to tau hyperphosphorylation in a rat model.

Tamunotonye Omoluabi¹, Zia Hasan¹, Jessie E Piche^1,2

¹Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.

|November 9, 2024

Summary

Alzheimer's disease research reveals that tau pathology in the locus coeruleus (LC) impairs neuron function and causes cognitive deficits. Blocking L-type calcium channels (LTCCs) may offer a therapeutic strategy for tau-induced neurodegeneration.

Keywords:

L‐type calcium channel electron microscopy locus coeruleus mitochondria single nuclei RNA sequencing tau

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Area of Science:

Neuroscience
Pathology
Genomics

Background:

The locus coeruleus (LC) is the first brain region affected by tau pathology in Alzheimer's disease (AD).
Degeneration of LC neurons correlates with cognitive decline in AD, but mechanisms remain unclear.
Pretangle tau, a precursor to neurofibrillary tangles (NFTs), is implicated in AD pathogenesis.

Purpose of the Study:

To investigate the molecular mechanisms underlying pretangle tau-induced degeneration of LC noradrenergic neurons.
To examine the impact of tau pathology on neuronal transcriptomics and mitochondrial function.
To explore potential therapeutic targets for mitigating tau-induced LC dysfunction.

Main Methods:

Transcriptomic and mitochondrial profiling of LC neurons in rats transduced with pseudophosphorylated human tau.
Assessment of spatial and olfactory learning deficits.
Evaluation of the effects of chronic L-type calcium channel (LTCC) blockade.

Main Results:

Tau hyperphosphorylation upregulated L-type calcium channel (LTCC) expression in LC neurons.
Impaired mitochondrial health and deficits in spatial and olfactory learning were observed.
Sex-dependent gene expression alterations were noted, and LTCC blockade ameliorated behavioral deficits and altered mitochondrial mRNA expression.

Conclusions:

Tau pathology in the LC leads to LTCC hyperactivity, mitochondrial dysfunction, and cognitive impairment.
LTCCs represent a potential therapeutic target for addressing early tau pathology in Alzheimer's disease.
Understanding tau's effects on the LC is crucial for developing effective AD treatments.