Neurodegeneration and Astrogliosis in the Human CA1 Hippocampal Subfield Are Related to hsp90ab1 and bag3 in Alzheimer's Disease.

Melania Gonzalez-Rodriguez,Isabel Ubeda-Banon,Alino Martinez-Marcos,Patricia Villanueva-Anguita,Sandra Villar-Conde,Veronica Astillero-Lopez,Alicia Flores-Cuadrado,Daniel Saiz-Sanchez

doi:10.3390/ijms23010165

Melania Gonzalez-Rodriguez, Isabel Ubeda-Banon + Show 6 more

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https://doi.org/10.3390/ijms23010165

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Abstract

Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, is characterized by executive dysfunction and memory impairment mediated by the accumulation of extracellular amyloid-β peptide (Aβ) and intracellular hyperphosphorylated tau protein. The hippocampus (HIPP) is essential for memory formation and is involved in early stages of disease. In fact, hippocampal atrophy is used as an early biomarker of neuronal injury and to evaluate disease progression. It is not yet well-understood whether changes in hippocampal volume are due to neuronal or glial loss. The aim of the study was to assess hippocampal atrophy and/or gliosis using unbiased stereological quantification and to obtain hippocampal proteomic profiles related to neurodegeneration and gliosis. Hippocampal volume measurement, stereological quantification of NeuN-, Iba-1- and GFAP-positive cells, and sequential window acquisition of all theoretical mass spectrometry (SWATH-MS) analysis were performed in AD and non-AD cases. Reduced hippocampal volume was identified using the Cavalieri probe, particularly in the CA1 region, where it correlated with neuronal loss and astrogliosis. A total of 102 downregulated and 47 upregulated proteins were identified in the SWATH-MS analysis after restrictive filtering based on an FC > 1.5 and p value < 0.01. The Hsp90 family of chaperones, particularly BAG3 and HSP90AB1, are closely related to astrocytes, indicating a possible role in degrading Aβ and tau through chaperone-mediated autophagy.

Highlights

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder [1] and is characterized by executive dysfunction and memory impairment [2,3]
The Cavalieri probe revealed a significant reduction in global hippocampal volume (Figure 1C), as well as a specific reduction in the volume of the CA1 region (Figure 1D)
To the best of our knowledge, this study is the first to use stereology to estimate the volume of hippocampal subfields and analyze neurons and glia using cell type-specific markers in these subfields in postmortem tissue from subjects with AD

Summary

Introduction

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder [1] and is characterized by executive dysfunction and memory impairment [2,3]. Hippocampal volume loss and medial temporal atrophy on magnetic resonance imaging (MRI) have been proposed as early signals of neuronal injury and as diagnostic criteria for AD [4,5,6]. MRI studies concerning volume loss in different hippocampal subfields (cornu ammonis fields CA1, CA2, and CA3 and the dentate gyrus, DG) have shown contradictory results. This discrepancy might be explained by the intrinsic difficulty of MRI techniques in delimiting the boundaries of the hippocampal subfields [7,8]. Postmortem studies using stereological approaches have shown preferential neural loss in the CA1 subfield [11,12,13,14], but neither neural nor glial-specific markers have been used

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