Apolipoprotein E4 is Associated with Primary Localized Cutaneous Amyloidosis

Apolipoprotein E4 is Associated with Primary Localized Cutaneous Amyloidosis
- Journal of Investigative Dermatology

Received 18 October 2001; Revised 11 February 2002; Accepted 19 February 2002.

Apolipoprotein E (apoE) is a lipid transport protein, which is a component of lipoproteins, such as very low density lipoprotein, intermediate density lipoprotein, high density lipoprotein, and chylomicron. ApoE is also produced and secreted in the skin, and is implicated to play roles in epidermal differentiation and proliferation (^{Barra et al, 1994}).

We have reported that apoE was a component of amyloid deposits of primary localized cutaneous amyloidosis (PLCA) using immunohistochemistry, immunogold electron microscopy, and immunoblotting (^{Furumoto et al, 1998}). PLCA, lichen amyloidosus, and macular amyloidosis are characterized by the finding that the amyloid deposits are limited to the papillary dermis (^{Kumakiri and Hashimoto, 1979}). There is a hypothesis that the precursor protein of PLCA might be keratin protein from epidermal keratinocytes (^{Hashimoto et al, 1990}). The pathogenesis of PLCA, however, remains undetermined and the amyloid fibril protein has not been identified. There are three common alleles for apoE, e2, e3, and e4, and their gene products are apoE2, apoE3, and apoE4, respectively (^{Mahley, 1988}). In this study, we investigated whether the phenotypic variation of apoE is associated with PLCA.

Fourteen Japanese patients (four females and 10 males) with PLCA were studied (mean age, 53 years; range, 26–82 years, Table I). The control group consisted of 100 healthy unrelated Japanese individuals randomly chosen from volunteers (mean age, 34.4 years; range, 21–83 years). Cutaneous amyloidosis was diagnosed clinically and histopathologically. Sera obtained from the peripheral venous blood samples were frozen at -80°C until use. Phenotypes of apoE were examined using analytical isoelectric focusing followed by immunoblotting with goat anti-apoE antibody and alkaline phosphatase-conjugated rabbit antigoat IgG (^{Furumoto et al, 1997}). Differences in apoE phenotype frequencies between the patients and control group were tested by the Chi-squared test with Yates' correction.

Table I - Details of patients with primary localized cutaneous amyloidosis. Clinical data and phenotypes of apolipoprotein E.

Full table

There are six of the most common phenotypes of apoE, E4/4, E3/3, E2/2, E4/3, E4/2, and E3/2. As shown in Table I, nine of 14 patients (64.3%) with PLCA have apoE4/4 or E4/3 phenotype, whereas 18 of 100 (18%) of controls have apoE4/4 or E4/3 phenotype. The phenotype frequency of apoE4/3 in PLCA was significantly higher than in healthy controls (57% in PLCA vs. 17% in control, p <0.01), and this elevation was based on the increased frequency of e4 allele (0.357 in PLCA vs. 0.095 in control; Table II).

Table II - ApoE phenotypes and allele frequencies in PLCA.

Full table

Our results indicate that the e4 allele is increased in frequency in PLCA. The e4 allele frequency in the Japanese population is 0.11, which is similar to that of Caucasians (^{Breslow, 1988}). ApoE4 is linked to the pathogenesis of Alzheimer's disease (AD), and the allele frequency in the AD population is significantly higher (3-fold) than that of controls (0.38 vs. 0.122) (^{Poirier et al, 1993}).

ApoE is associated with amyloid plaque of the many amyloid- forming diseases (^{Namba et al, 1991;Wisniewski and Frangione, 1992;Strittmatter et al, 1993}). Recently, it has been reported that carboxyl-terminal-truncated fragments of apoE4, especially apoE4 (272–299), which were generated inside cultured neurons and in AD brains resulted in large, filamentous intracellular inclusions resembling neurofibrillary tangles in AD brain (^{Huang et al, 2001}). The apoE4 fragments interact with phosphorylated tau and phosphorylated neurofilaments of high molecular weight. Therefore, it is suggested that apoE4 molecule plays an important role for the development and maintaining of amyloid deposit in AD brain. The function of apoE in epidermis is unknown, but it is naturally secreted by keratinocytes (^{Fenjves et al, 1989;Gordon et al, 1989}). Our result indicates that apoE4 molecule synthesized by epidermal keratinocytes is strongly related to the pathogenesis of cutaneous amyloidosis, especially formation of amyloid fibrils.
 

Hiroko Furumoto, Takahiro Shimizu^†, Masahiko Muto, Yumiko Hashimoto^* and Kazuyuki Nakamura

1. Departments of Biochemistry and Yamaguchi University School of Medicine, Ube, Japan
2. ^*Departments of Biochemistry and Dermatology, Yamaguchi University School of Medicine, Ube, Japan
3. ^†Division of Dermatology, Saiseikai Yamaguchi General Hospital, Yamaguchi, Japan

Correspondence: Prof Kazuyuki Nakamura, Department of Biochemistry, Yamaguchi University School of Medicine, Minami-kogushi, Ube 755-8505, Japan. Email: nakamura@po.cc.yamaguchi-u.ac.jp