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

Article type: Research Article

Authors: Mi, Zhiping^{a; b; 1} | Abrahamson, Eric E.^{a; b; 1} | Ryu, Angela Y.^a | Malek-Ahmadi, Michael^{c; d} | Kofler, Julia K.^e | Fish, Kenneth N.^f | Sweet, Robert A.^{a; f} | Villemagne, Victor L.^f | Schneider, Julie A.^g | Mufson, Elliott J.^{c; h} | Ikonomovic, Milos D.^{a; b; f; *}

Affiliations: [a] Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA | [b] Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA | [c] Banner Alzheimer’s Institute, Phoenix, AZ, USA | [d] Department of Biomedical Informatics, University of Arizona College of Medicine, Phoenix, AZ, USA | [e] Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA | [f] Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA | [g] Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA | [h] Departments of Translational Neurosciences and Neurology, Barrow Neurological Institute, Phoenix, AZ, USA

Correspondence: [*] Correspondence to: Milos D. Ikonomovic, MD, University of Pittsburgh School of Medicine, Thomas Detre Hall of the WPIC, Room 1421, 3811 O’Hara Street, Pittsburgh, PA 15213–2593, USA. Tel.: +1 412 802 3004; Fax: +1 412 648 1239; E-mail: ikonomovicmd@upmc.edu.

Note: [1] These authors contributed equally to this work.

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

DOI: 10.3233/JAD-221063

Journal: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 227-246, 2023