Brain region-specific dopamine receptor changes and astrocyte activation influence tau pathology through CDK5 in Alzheimer's disease models

Oct 29, 2025Journal of Alzheimer's disease : JAD

Changes in dopamine receptors and support cell activity in specific brain areas may affect tau buildup through CDK5 in Alzheimer's models

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Abstract

In the brains of 5XFAD mice, Gs-coupled dopamine receptors (DR1 and DR5) were upregulated, while Gi-coupled receptors (DR2, DR3, and DR4) were downregulated.

Changes in dopamine receptor expression may alter signaling pathways related to and neurodegeneration in Alzheimer's disease.
Aβ exposure in neuronal models replicated the receptor subtype changes seen in the animal model.
Increased expression of DR1 and DR5 was associated with elevated levels of and tau phosphorylation.
The cortex exhibited greater vulnerability to degeneration from Aβ, while the hippocampus showed increased susceptibility to inflammation and tau pathology.

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BackgroundThe abnormal extracellular accumulation of amyloid-β (Aβ) plaques and intracellular tau inclusions are hallmarks of early events in the pathogenesis of Alzheimer's disease (AD). Although growing evidence implicates neurotransmitter dysregulation in AD-associated neurodegeneration, the influence of these pathological hallmarks on dopaminergic signaling remains poorly understood. This study reports changes in dopamine receptor (DR), Aβ, and astrocyte distribution in the cortex and hippocampus of 5XFAD mice.ObjectiveTo investigate how Aβ pathology alters dopamine receptor subtype expression in the AD brain and neuronal models, and whether this contributes to and activation.MethodsWe examined DR1-DR5 expression and localization in the cortex and hippocampus of 5XFAD mice using immunohistochemistry, qPCR, and western blot. SH-SY5Y cells were differentiated with retinoic acid and treated with Aβ; MC-65 cells produced endogenous Aβ via tetracycline withdrawal. DR1, DR2, and DR3 agonists were used to assess effects on cAMP, CDK5, and tau phosphorylation.ResultsIn AD brains, Gs-coupled DR1 and DR5 were upregulated, while Gi-coupled DR2, DR3, and DR4 were downregulated at mRNA and protein levels. SH-SY5Y and MC-65 cells recapitulated these subtype-specific changes following Aβ exposure. In the cortex, receptor alterations were implicated in increased CDK5 and tau phosphorylation. DR activation modulated cAMP and kinase pathways in a receptor- and cell-specific manner. The cortex showed greater vulnerability to Aβ-associated degeneration, whereas the hippocampus was more susceptible to inflammation and tau pathology.ConclusionsThese findings reveal a role for DR subtypes in regulating tau phosphorylation and CDK5, with implications for AD-related cognitive dysfunction. 1-42

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230%

Increase in astrocytes in cortex

Increase in GFAP-positive astrocytes in the cortex of 5XFAD mice.

80%

Increase in astrocytes in hippocampus

Increase in GFAP-positive astrocytes in the hippocampus of 5XFAD mice.

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Brain region-specific dopamine receptor changes and astrocyte activation influence tau pathology through CDK5 in Alzheimer's disease models

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