Modulation of SPARC/Hevin Proteins in Alzheimer’s Disease Brain Injury

Abstract

Alzheimer’s disease (AD) is an age-related progressive form of dementia that features neuronal loss, intracellular tau, and extracellular amyloid-β (Aβ) protein deposition. Neurodegeneration is accompanied by neuroinflammation mainly involving microglia, the resident innate immune cell population of the brain. During AD progression, microglia shift their phenotype, and it has been suggested that they express matricellular proteins such as secreted protein acidic and rich in cysteine (SPARC) and Hevin protein, which facilitate the migration of other immune cells, such as blood-derived dendritic cells. We have detected both SPARC and Hevin in postmortem AD brain tissues and confirmed significant alterations in transcript expression using real-time qPCR. We suggest that an infiltration of myeloid-derived immune cells occurs in the areas of diseased tissue. SPARC is highly expressed in AD brain and collocates to Aβ protein deposits, thus contributing actively to cerebral inflammation and subsequent tissue repair, and Hevin may be downregulated in the diseased state. However, further research is needed to reveal the exact roles of SPARC and Hevin proteins and associated signaling pathways in AD-related neuroinflammation. Nevertheless, normalizing SPARC/Hevin protein expression such as interdicting heightened SPARC protein expression may confer a novel therapeutic opportunity for modulating AD progression.

A comprehensive systematic review of CSF proteins and peptides that define Alzheimer’s disease

“…Specifically, high levels of SPRC have been shown in AD brain wherein it colocalizes to Aβ protein depots. It has been proposed that SPRC contributes to cerebral inflammation and subsequent tissue repair [31].…”

Osteonectin regulates the extracellular matrix mineralization of osteoblasts through P38 signaling pathway

“…During matrix mineralization, osteoblasts synthesize and secrete type I collagen and noncollagen proteins; the framework formed by collagen fibers is the structural basis of bone mineralization, while noncollagen proteins are engaged in hydroxyapatite deposition; osteonectin is one of important noncollagen proteins, also known as SPARC (secreted protein acidic and rich in cysteine) or BM‐40 (Bradshaw, ; Murphy‐Ullrich & Sage, ), it has a high affinity with type I collagen and hydroxyapatite (Termine et al, ) and is involved in the whole process of bone matrix mineralization (Nakase et al, ). Extracellular matrix plays a key role in regulating cell adhesion and motility; in the study of diazepam leading to cleft lip‐palate, it was found that the basic cause of the disease was the change of extracellular matrix components (Marinucci et al, ); osteonectin is also a modular extracellular matrix protein that functions more as a regulator of cell behavior than as a structural part of the matrix, including tissue remodeling, repair, development, and cell turnover (Bradshaw & Sage, ); recent studies have shown that osteonectin has positive effects on brain injury and myocarditis (Deckx et al, ; Strunz et al, ), and is also an meaningful marker for the diagnosis, treatment, and prognosis of malignant tumors (Fukushima, Tamura, Nakagawa, & Itoh, ; Luo et al, ; Ribeiro, Sousa, Brekken, & Monteiro, ). The importance of osteonectin for normal remodeling and maintenance of bone mass has been fully verified by numerous studies of osteonectin‐null mice (Delany & Hankenson, ; Delany, Kalajzic, Bradshaw, Sage, & Canalis, ; Kapinas et al, ; Van Dijk & Sillence, ).…”

Blood–Brain Barrier Degradation and the Implication of SPARC Protein as a Potential Therapeutic Target for Alzheimer’s Disease

“…The proteins are primarily expressed in immune cells. While both SPARC and Hevin are produced by microglia (7) and astrocytes (61), Hevin is produced only by some neurons (62). Postmortem examination of the brains of AD and control individuals found that there is a notable upregulation of SPARC and downregulation of Hevin in the AD brains.…”

“…While the integrity of the BBB is tightly regulated, emerging evidence implicates the matricellular proteins, secreted protein acidic and rich in cysteine (SPARC), and Hevin, as having a role in regulating BBB permeability. This chapter discusses the effects of various AD risk factors on BBB permeability, with emphasis on SPARC, which is upregulated in AD brain tissue (6,7). Since the SPARC protein enhances BBB permeability, promotes neuroinflammation, and prolongs pro-inflammatory M1 phase of microglia, its potential as a druggable target is also discussed.…”