Lipopolysaccharide, Identified Using an Antibody and by PAS Staining, Is Associated With Corpora amylacea and White Matter Injury in Alzheimer's Disease and Aging Brain.

Xinhua Zhan,Marisa Hakoupian,Frank R Sharp,Lee-Way Jin

doi:10.3389/fnagi.2021.705594

Xinhua Zhan, Marisa Hakoupian + Show 2 more

Open Access

https://doi.org/10.3389/fnagi.2021.705594

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Abstract

Corpora amylacea (CA) increase in number and size with aging. Their origins and functions remain unknown. Previously, we found that Alzheimer's disease (AD) brains have more CA in the periventricular white matter (PVWM) compared to aging controls. In addition, CA is associated with neurodegeneration as indicated by colocalization of degraded myelin basic protein (dMBP) with periodic acid-Schiff (PAS), a CA marker. We also found that bacterial lipopolysaccharide is present in aging brains, with more LPS in AD compared with controls. Periodic acid-Schiff staining is used to identify CA by virtue of their high polysaccharide content. Despite the growing knowledge of CA as a contributor to AD pathology, the molecules that contribute to the polysaccharides in CA are not known. Notably, lipopolysaccharides (LPS) are important cell-surface polysaccharides found in all Gram-negative bacteria. However, it is unknown whether PAS could detect LPS, whether the LPS found in aging brains contribute to the polysaccharide found in CA, and whether LPS associate with myelin injury. In this study, we found that aging brains had a myelin deficit zone (MDZ) adjacent to the ventricles in PVWM. The MDZ contained vesicles, most of which were CA. LPS and dMBP levels were higher in AD than in control brains. LPS was colocalized with dMBP in the vesicles/CA, linking white matter injury with a bacterial pro-inflammatory molecule. The vesicles also contained oxidized fibers, C-reactive protein, NG2, and GALC, markers of oligodendrocyte precursor cells (OPCs) and oligodendrocyte cells (OLs), respectively. The vesicles/CA were surrounded by dense astrocyte processes in control and AD brains. LPS was co-localized with CA by double staining of PAS with LPS in aging brains. The relationship of LPS with PAS staining was confirmed by PAS staining of purified LPS on nitrocellulose membranes. These findings reveal that LPS is one of the polysaccharides found in CA which can be stained with PAS. In addition, vesicles/CA are associated with oxidized and damaged myelin. The LPS in these vesicles/CA may have contributed to this oxidative myelin damage and may have contributed to oxidative stress to OPCs and OLs which could impair the ability to repair damaged myelin in AD and control brains.

Highlights

Corpora amylacea are glycoprotein-containing inclusions found in the aging brain and other organs
A recent proteomic analysis identified several peptides associated with Gram-negative and lipopolysaccharide (Peters et al, 2005) containing proteobacteria in Corpora amylacea (CA) (Pisa et al, 2018). These findings suggest that CA are not just inert structures that occur in the brain but may be part of an orchestrated immune system response that involves vascular components, damage to white matter and adjacent brain tissues, and microbial components including Gram negative bacteria
Our previous studies showed the presence of degraded myelin basic protein (dMBP) in both control and Alzheimer’s disease (AD) brains, though there was more dMBP in AD brains (Zhan et al, 2014)

Summary

Introduction

Corpora amylacea are glycoprotein-containing inclusions found in the aging brain and other organs. Components from blood plasma, blood cells, and other cells of the human body are identified in the CA of human brains These components include ubiquitin (Sahlas et al, 2002), heme oxygenase-1 (Sahlas et al, 2002), thrombospondin (Meng et al, 2009), complement (Singhrao et al, 1995), S100 proteins (Hoyaux et al, 2000), and calprotectin, a soluble protein contained in neutrophil granules. A recent proteomic analysis identified several peptides associated with Gram-negative and lipopolysaccharide (Peters et al, 2005) containing proteobacteria in CA (Pisa et al, 2018) These findings suggest that CA are not just inert structures that occur in the brain but may be part of an orchestrated immune system response that involves vascular components, damage to white matter and adjacent brain tissues, and microbial components including Gram negative bacteria

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