Vesicular Glutamate Transporter Changes in the Cortical Default Mode Network During the Clinical and Pathological Progression of Alzheimer's Disease

Authors

Zhiping Mi, Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Eric E. Abrahamson, Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Angela Y. Ryu, Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Michael Malek-Ahmadi, Banner Alzheimer's Institute, Phoenix, AZ, USA.
Julia K. Kofler, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Kenneth N. Fish, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Robert A. Sweet, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Victor L. Villemagne, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Julie A. Schneider, Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Elliott J. Mufson, Banner Alzheimer's Institute, Phoenix, AZ, USA.
Milos D. Ikonomovic, Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Document Type

Article

Abstract

BACKGROUND: Altered glutamatergic neurotransmission may contribute to impaired default mode network (DMN) function in Alzheimer's disease (AD). Among the DMN hub regions, frontal cortex (FC) was suggested to undergo a glutamatergic plasticity response in prodromal AD, while the status of glutamatergic synapses in the precuneus (PreC) during clinical-neuropathological AD progression is not known. OBJECTIVE: To quantify vesicular glutamate transporter VGluT1- and VGluT2-containing synaptic terminals in PreC and FC across clinical stages of AD. METHODS: Unbiased sampling and quantitative confocal immunofluorescence of cortical VGluT1- and VGluT2-immunoreactive profiles and spinophilin-labeled dendritic spines were performed in cases with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or moderate-severe AD (sAD). RESULTS: In both regions, loss of VGluT1-positive profile density was seen in sAD compared to NCI, MCI, and mAD. VGluT1-positive profile intensity in PreC did not differ across groups, while in FC it was greater in MCI, mAD, and sAD compared to NCI. VGluT2 measures were stable in PreC while FC had greater VGluT2-positive profile density in MCI compared to sAD, but not NCI or mAD. Spinophilin measures in PreC were lower in mAD and sAD compared to NCI, while in FC they were stable across groups. Lower VGluT1 and spinophilin measures in PreC, but not FC, correlated with greater neuropathology. CONCLUSION: Frank loss of VGluT1 in advanced AD relative to NCI occurs in both DMN regions. In FC, an upregulation of VGluT1 protein content in remaining glutamatergic terminals may contribute to this region's plasticity response in AD.

Keywords

Alzheimer’s disease, amyloid, glutamate, plasticity, synapse, vesicular glutamate transporter

Publication Date

5-19-2023

Publication Title

Journal of Alzheimer's disease : JAD

E-ISSN

1875-8908

PubMed ID

37212097

Digital Object Identifier (DOI)

10.3233/JAD-221063

Recommended Citation

Mi, Zhiping; Abrahamson, Eric E.; Ryu, Angela Y.; Malek-Ahmadi, Michael; Kofler, Julia K.; Fish, Kenneth N.; Sweet, Robert A.; Villemagne, Victor L.; Schneider, Julie A.; Mufson, Elliott J.; and Ikonomovic, Milos D., "Vesicular Glutamate Transporter Changes in the Cortical Default Mode Network During the Clinical and Pathological Progression of Alzheimer's Disease" (2023). Translational Neuroscience. 2299.
https://scholar.barrowneuro.org/neurobiology/2299