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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 .