Dopaminergic dysfunction in the 3xTg-AD mice model of Alzheimer\u2019s disease

Yesica Gloria,Philippe Millet,Stergios Tsartsalis,Benjamin B Tournier,Kelly Ceyzériat

doi:10.1038/s41598-021-99025-1

Abstract

Alzheimer’s disease (AD) is characterized by amyloid (Aβ) protein aggregation and neurofibrillary tangles accumulation, accompanied by neuroinflammation. With all the therapeutic attempts targeting these biomarkers having been unsuccessful, the understanding of early mechanisms involved in the pathology is of paramount importance. Dopaminergic system involvement in AD has been suggested, particularly through the appearance of dopaminergic dysfunction-related neuropsychiatric symptoms and an overall worsening of cognitive and behavioral symptoms. In this study, we reported an early dopaminergic dysfunction in a mouse model presenting both amyloid and Tau pathology. 3xTg-AD mice showed an increase of postsynaptic D2/3R receptors density in the striatum and D2/3-autoreceptors in SN/VTA cell bodies. Functionally, a reduction of anxiety-like behavior, an increase in locomotor activity and D2R hyper-sensitivity to quinpirole stimulation have been observed. In addition, microglial cells in the striatum showed an early inflammatory response, suggesting its participation in dopaminergic alterations. These events are observed at an age when tau accumulation and Aβ deposits in the hippocampus are low. Thus, our results suggest that early dopaminergic dysfunction could have consequences in behavior and cognitive function, and may shed light on future therapeutic pathways of AD.

Highlights

Alzheimer’s disease (AD) is characterized by amyloid (Aβ) protein aggregation and neurofibrillary tangles accumulation, accompanied by neuroinflammation
To verify the hypothesis according to which dopaminergic transmission is impacted in early AD, we characterized in the midbrain and the striatum the markers of dopaminergic system, glial reactivity and behavioral effects in heterozygous 3xTg-AD mice at an age when pathological markers are weakly expressed (Aβ and Tau)
The quantification of D 2/3R density in the striatum of 12-month-old 3xTg-AD mice compared to age-matched control animals revealed a global upregulation of the receptor expression which did not differ between the CPu (DLS, DMS, VLS) and the NAcc (Acc, Acs) (Fig. 1a–c, genotype: F 1,40 = 11.65, p < 0.01; striatal subdivision: F 4,40 = 49.95, p < 0.001; genotype × striatal subdivision: F 4,40 = 0.74, p > 0.05)

Summary

Introduction

Alzheimer’s disease (AD) is characterized by amyloid (Aβ) protein aggregation and neurofibrillary tangles accumulation, accompanied by neuroinflammation. APP/ PS128,29, Tau[30] and mixed triple transgenic (3xTg-AD, A PPSWE, PS1M146V and TauP301L)[31,32,33,34,35,36] animal models have been shown to develop alterations in locomotor activity and this could result from changes in DA activity These first studies suggest the implication of dopaminergic dysfunction within the early stage of AD pathogenesis. To verify the hypothesis according to which dopaminergic transmission is impacted in early AD, we characterized in the midbrain and the striatum the markers of dopaminergic system (density of D 2/3R, TH and DAT, dopamine transporter), glial reactivity (astrocytes and microglia) and behavioral effects (locomotion and locomotor response to stimulation of D2R) in heterozygous 3xTg-AD mice at an age when pathological markers are weakly expressed (Aβ and Tau). The use of heterozygous mice is advantageous to distinguish the onset of pathological signs since they are less severely manifested, and the neuropathology develops slower than in homozygous mice[37,38,39]

Methods

Results

Conclusion