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INVESTIGATIVE REPORT ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica
Overexpression of Amyloid Precursor Protein Promotes the Onset of Seborrhoeic Keratosis and is Related to Skin Ageing
Yuanying LI #, Yu WANG #, Wei ZHANG #, Leiwei JIANG, Wenming ZHOU, Zhi LIU, Shijun LI and Hongguang LU Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
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These authors contributed equally to this paper.
Seborrhoeic keratosis is an age-related skin disease. Amyloid precursor protein( APP) plays an important role in the pathogenesis of age-related Alzheimer’ s disease. The aim of this study was to elucidate the expression characteristics of APP in seborrhoeic keratosis tissues( n = 50), and explore whether the production of APP is related to the onset of seborrhoeic keratosis and skin ageing, including ultraviolet( UV)- induced ageing, as observed in normal skin( n = 79). The results of immunohistochemistry, Western blotting and quantitative real-time PCR showed that APP and its downstream products( i. e. amyloid-β42) were more highly expressed in seborrhoeic keratosis than in paired adjacent normal skin tissues. In contrast, the expression of its key secretase( i. e. β-secretase1) was generally low. Furthermore, APP expression was higher in UV-exposed than non-exposed skin sites, and expression in the older age group( 61 – 85 years) was greater than that in the younger age group( 41 – 60 years) in seborrhoeic keratosis tissues( p < 0.05). APP expression correlated positively with age in epidermis( p < 0.05), but not in dermis. These findings suggest that overexpression of APP may promote the onset of seborrhoeic keratosis and is a marker of skin ageing and UV damage. Further research will elucidate whether therapeutic mitigation of increased levels of APP in the skin might delay the onset of seborrhoeic keratosis and skin ageing.
Key words: amyloid precursor protein; seborrhoeic keratosis; amyloid-β42; β-secretase1( BACE1).
Accepted Feb 20, 2018; Epub ahead of print Feb 28, 2018 Acta Derm Venereol 2018; 98: 594 – 600.
Corr: Hongguang Lu, Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550001, China. E-mail: hongguanglu @ hotmail. com
Seborrhoeic keratosis( SK) is one of the most common benign epithelial skin tumours. SK is caused by the abnormal proliferation of epidermal keratinocytes( KCs)( 1). SK lesions are often round or oval-shaped, yellowish, grey-brown or black, usually elevated, and appear to be stuck on the skin surface. They may arise on any area of the skin surface, except for the palms and soles( 1, 2). Histologically, SK is composed mainly of basaloid and squamous cells( 3). Both UV exposure and old age are independent risk factors for SK( 1), which is often considered as a sign of skin ageing, including photoaging
( 4). SK is causally related to somatic mutations in FGFR3 and a few other genes expressed in human keratinocytes( 5). Like senile Alzheimer’ s disease( AD), the prevalence of SK tends to increase with age( 1).
It is well-known that amyloid precursor protein( APP) is a key player in the pathogenesis of senile AD. APP is an integral type I transmembrane protein, which contains at least 19 exons that are located on chromosome 21( 21q21.2-3)( 6, 7). The cDNA sequence of human APP was first cloned from a brain tissue library( 6, 8). APP is processed by at least 3 proteases, i. e. α-, β- and γ-secretases, via the amyloidogenic and nonamyloidogenic pathways( 9). In the amyloidogenic path way cleavage by β-secretase( BACE) and γ-secretase releases amyloid-β42( Aβ42), which plays an important role in early pathological events in early-onset familial AD and sporadic age-related AD( 8, 10). Moreover, previous studies have shown that other age-related diseases, such as Parkinson’ s disease and age-related macular degeneration, are accompanied by high levels of expression of APP( 11 – 14). However, the biological activity of APP in SK is unknown. There is substantial evidence to support that APP is expressed not only in neuronal cells of the brain, but also in non-neuronal cells, such as KCs( 7, 15 – 18). In skin tissue, researchers have observed that APP is highly expressed within the basal cell layer of mammalian epidermis( 9). Functionally, both full-length APP and the soluble form( sAPPα), cleaved by α-secretase via the non-amyloidogenic pathway, can enhance proliferation, differentiation and migration of KCs( 9). Although APP is up-regulated in some proliferative skin diseases, such as psoriasis( 9), it remains unclear whether expression of APP is associated with the development of age-related skin diseases and skin ageing.
The aim of this study was to examine the expression of APP, BACE1 and Aβ42 in SK, and to elucidate the relationship between expression of APP and skin ageing.
METHODS Collection of clinical tissue samples
A total of 129 subjects( 50 patients with SK and 79 healthy controls) were recruited at the Department of Dermatology, Affiliated Hospital of Guizhou Medical University between January 2015 and July 2016. SK tissues and paired adjacent normal skin tissues( PANST) were collected from the 50 patients with SK. Diagnoses of all patients were based on clinical examination and skin biopsy doi: 10.2340 / 00015555-2911 Acta Derm Venereol 2018; 98: 594 – 600
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2018 Acta Dermato-Venereologica.