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The presenilin-1 (PS-1) gene was identified as one of the causative genes in early onset familial Alzheimer’s disease and located on chromosome 14.1 Recently, we found that the PS-1mRNA concentrations in skin fibroblasts of patients with mild Alzheimer’s disease were significantly higher than those of controls.2 Down’s syndrome has lesions similar to those in Alzheimer’s disease, and most patients with Down’s syndrome develop dementia. To our knowledge, there are no reports on the expression of PS-1 mRNA in Down’s syndrome. In this study, we used northern blot analysis to analyse the expression of PS-1 mRNA in cultured skin fibroblasts taken from living patients with Down’s syndrome.
The study population consisted of 12 patients with Down’s syndrome (age 32.8 (SD 25.8); eight patients with dementia and four patients without dementia); 18 patients with sporadic Alzheimer’s disease (age 57.5 (SD 24.5); six patients with mild, nine with moderate, and three with severe degrees of dementia) who had no mutation of APP, PS-1, and PS2 genes; and 22 neurological patients without dementia as controls (age 41.8 (SD 34.8)).
The diagnosis of dementia was based on interviews, internal medical findings, neurological examinations, cranical CT, general haematological tests, blood chemical tests, EEG, the mini mental state examination, Barthel index (daily activities), and surveillance of daily activities. Patients who carried trisomy on chromosome 21 were diagnosed as having Down’s syndrome. Patients who satisfied the diagnostic criteria of the Down’s syndrome M-III-R and NINCDS-ADRDA criteria and those scoring ⩽4 on Hachinski’s ischaemic score were diagnosed as having Alzheimer’s disease. The severity of disease was established according to the Down’s syndrome M-III-R criteria of mild, moderate, or severe. Skin fibroblasts were prepared from the patients as follows. After the patient’s and his or her family’s consent had been obtained, skin fibroblasts were collected from the brachial skin, cultured, and incubated according to the method of Ohno et al.3 Northern blot analysis was performed by the method of Goldberg.4 We quantified the relative ratios of densities of PS-1 mRNA to β-actin mRNA using a densitometer. We evaluated differences between groups by the Mann-Whitney test, .
There was no significant association between PS-1 mRNA and age in CTL. The relative ratios of densities of PS-1 mRNA to β-actin mRNA in fibroblasts of patients with Down’s syndrome were significantly higher than those of the controls (figure). However, there was no significant difference between these values for patients with moderate to severe dementia and those of the controls.
These findings suggest that the PS-1 gene may play an important part in the development of Alzheimer’s disease in the early stages, and that PS-1 may also be closely associated with dementia in Down’s syndrome. Although it is well known that patients with Down’s syndrome carry trisomy on chromosome 21, the cause for the dementia in patients with Down’s syndrome is unknown. We consider that both Alzheimer’s disease and Down’s syndrome may share the same mechanism, a high concentration of PS-1 mRNA leading to the development of dementia. Further studies are necessary to clarify the mechanisms relating to these high concentrations of PS-1 mRNA in Down’s syndrome as well as in Alzheimer’s disease.