Neurite-Outgrowth Regulating Functions of the Amyloid Protein Precursor of Alzheimer's Disease*

Small, David H.; Clarris, H.L.; Williamson, Timothy G.; Reed, G.; Key, Brian; Mok, Su San; Beyreuther, Konrad; Masters, Colin L.; Nurcombe, Victor

doi:10.3233/jad-1999-14-508

Cited by 56 publications

(36 citation statements)

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“…Full-length membrane-bound ␤PP may function as a cell surface receptor capable of interacting with G-proteins (Nishimoto et al, 1993) and in cell adhesion. The latter function is consistent with the binding of ␤PP with laminin and proteoglycans (Small et al, 1996). Which of these diverse functions predominates in brain is unclear.…”

supporting

confidence: 59%

Cell Surface Amyloid β-Protein Precursor Colocalizes with β1 Integrins at Substrate Contact Sites in Neural Cells

1997

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Amyloid ␤-protein (A␤), the principal constituent of the senile plaques seen in Alzheimer's disease (AD), is derived by proteolysis from the ␤-amyloid precursor protein (␤PP). The distribution and trafficking of cell surface ␤PP are of particular interest because some of these molecules are direct precursors of secreted A␤ and because the localization of ␤PP at the cell surface may be related directly to its physiological functions. Recently, we reported that, in cultured hippocampal neurons, cell surface ␤PP is preferentially expressed on axons in a striking discontinuous pattern. In this study, we describe the colocalization of cell surface ␤PP and integrins in primary cultured cells. In rat hippocampal neurons, cell surface ␤PP was colocalized selectively with ␣1␤1 and ␣5␤1 integrin heterodimers at these characteristic segmental locations. In rat cortical astrocytes, both cell surface ␤PP and ␤1 integrin were located at the cell periphery in the "spreading" stage shortly after plating. In "flattened" astrocytes cultured for several days, ␤PP was found in punctate deposits called point contacts. In these sites, ␤PP was colocalized with ␣1␤1, but not with ␣5␤1 integrin heterodimers, the latter of which were situated at focal contact sites. In both neurons and astrocytes examined after shearing, clathrin and ␣-adaptin were colocalized with ␤PP on the surface that directly contacts the substratum. These results are consistent with the putative role of ␤PP in cell adhesion and suggests that ␤PP either interacts with selected integrins or shares similar cellular machinery to promote cell adhesion. Key words: amyloid ␤-protein precursor; amyloid ␤-protein; integrins; cell adhesion; clathrin; substrate attachment; point contactsAlzheimer's disease (AD) is a progressive, neurodegenerative disorder characterized by the extracellular deposition of the 39 -43 amino acid amyloid ␤-protein (A␤) in the brain parenchyma (Selkoe, 1994). A␤ is derived by proteolytic cleavages from the ␤-amyloid precursor protein (␤PP) (Kang et al., 1987). Constitutive cleavage of ␤PP by "␣-secretase" occurring in vivo and in vitro results in the secretion of the N-terminal ectodomain ␤PP S . The ubiquitous ␣-secretase cleavage occurs within the A␤ region and therefore precludes the generation of an intact A␤ peptide . In contrast to most non-neural cells, neurons and glia secrete relatively small amounts of ␤PP S for unclear reasons (Haass et al., 1991). Some ␤PP molecules not cleaved on the cell surface are internalized and targeted to endosomes and lysosomes. A smaller population of ␤PP molecules seems to be recycled back to the surface for secretion or internalization . Both the secretory and endocytic pathways have been shown to contribute to A␤ released into medium by cultured cells, although endocytic processing seems to be the predominant source (Koo and Squazzo, 1994).The physiological role of ␤PP remains to be defined. Proposed functions for ␤PP S include neurite-promoting properties, wound healing, cell adhesion, cell growth and diff...

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supporting

confidence: 59%

Cell Surface Amyloid β-Protein Precursor Colocalizes with β1 Integrins at Substrate Contact Sites in Neural Cells

1997

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“…The large N-terminal domain of APP (residues 28 -123) contains cysteine-rich regions and a heparinbinding site and shows similarities to well known growth factors and can therefore be classified as a member of the cysteine-rich growth factor superfamily (44). The extracellular domain interacts with matrix proteins and heparan sulfate proteoglycans reflecting its role in migration, adhesion, and cell-matrix and cell-cell interactions (45)(46)(47)(48). Recently, it has been shown that APP is up-regulated in several cancer species, including pancreatic (15), colon (14), melanoma (49), and prostate cancer (17), as well as oral squamous cell carcinoma (15), and has growth-promoting features.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Venkataramani

Roßner

Iffland

et al. 2010

Journal of Biological Chemistry

111

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The ␤-amyloid precursor protein (APP) represents a type I transmembrane glycoprotein that is ubiquitously expressed. In the brain, it is a key player in the molecular pathogenesis of Alzheimer disease. Its physiological function is however less well understood. Previous studies showed that APP is up-regulated in prostate, colon, pancreatic tumor, and oral squamous cell carcinoma. In this study, we show that APP has an essential role in growth control of pancreatic and colon cancer. Abundant APP staining was found in human pancreatic adenocarcinoma and colon cancer tissue. Interestingly, treating pancreatic and colon cancer cells with valproic acid (VPA, 2-propylpentanoic acid), a known histone deacetylase (HDAC) inhibitor, leads to up-regulation of GRP78, an endoplasmic reticulum chaperone immunoglobulin-binding protein. GRP78 is involved in APP maturation and inhibition of tumor cell growth by down-regulation of APP and secreted soluble APP␣. Trichostatin A, a pan-HDAC inhibitor, also lowered APP and increased GRP78 levels. In contrast, treating cells with valpromide, a VPA derivative lacking HDAC inhibitory properties, had no effect on APP levels. VPA did not modify the level of epidermal growth factor receptor, another type I transmembrane protein, and APLP2, a member of the APP family, demonstrating the specificity of the VPA effect on APP. Small interfering RNA-mediated knockdown of APP also resulted in significantly decreased cell growth. Based on these observations, the data suggest that APP downregulation via HDAC inhibition provides a novel mechanism for pancreatic and colon cancer therapy. ␤-Amyloid precursor protein (APP)2 is a highly conserved single transmembrane protein (type I) with a receptor-like structure and consists of a heterogeneous group of proteins migrating between 110 and 135 kDa (1, 2). The heterogeneity is due to alternative splicing, leading to eight distinct isoforms (namely APP677, APP695, APP696, APP714, APP733, APP751, APP752, and APP770), as well as by a variety of post-translational modifications, including O-and N-glycosylation, sulfation, and phosphorylation. APP isoforms exist as immature (N-glycosylated) and mature (N-and O-glycosylated, tyrosylsulfated) species. Immature APP localizes in the endoplasmic reticulum and cis-Golgi, and the mature APP form preferentially localizes in the trans-Golgi network, secretory and endocytic vesicles, and at the plasma membrane (3, 4).APP695 is the most common isoform in the central nervous system, whereas APP751 and APP770 are predominantly expressed in non-neuronal cells (5). The key event in the pathogenic cascade in Alzheimer disease is the amyloidogenic pathway characterized by subsequent cleavage of APP by the enzyme ␤-secretase and further processing by ␥-secretase, which finally leads to the generation of A␤ peptides. However, the predominant route of APP processing consists of successive cleavages by ␣-and ␥-secretases in non-neuronal cells (6, 7). The cleavage of APP at Lys 16 -Leu 17 bond by ␣-secretase within the A␤ sequence ...

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“…In particular, binding of APP to extracellular proteoglycans has been suggested to play a role in inducing neurite outgrowth, and a peptide homologous to the APP heparin-binding domain blocked this effect (Small et al 1994(Small et al , 1999. Qiu et al found that when APP-transfected CHO cells were used as a substrate for the growth of primary rat hippocampal neurons, increased surface APP expression stimulated short-term neuronal adhesion and longer-term neurite outgrowth (Qiu et al 1995).…”

Section: Neural and Synapto-trophic Functionsmentioning

confidence: 99%

Physiological Functions of APP Family Proteins

Müller¹,

Zheng²

2011

Cold Spring Harbor Perspectives in Medicine

270

235

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Biochemical and genetic evidence establishes a central role of the amyloid precursor protein (APP) in Alzheimer disease (AD) pathogenesis. Biochemically, deposition of the b-amyloid (Ab) peptides produced from proteolytic processing of APP forms the defining pathological hallmark of AD; genetically, both point mutations and duplications of wild-type APP are linked to a subset of early onset of familial AD (FAD) and cerebral amyloid angiopathy. As such, the biological functions of APP and its processing products have been the subject of intense investigation, and the past 20þ years of research have met with both excitement and challenges. This article will review the current understanding of the physiological functions of APP in the context of APP family members.

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Neurite-Outgrowth Regulating Functions of the Amyloid Protein Precursor of Alzheimer's Disease*

Cited by 56 publications

References 0 publications

Cell Surface Amyloid β-Protein Precursor Colocalizes with β1 Integrins at Substrate Contact Sites in Neural Cells

Cell Surface Amyloid β-Protein Precursor Colocalizes with β1 Integrins at Substrate Contact Sites in Neural Cells

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Physiological Functions of APP Family Proteins

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