Lymphocytes from Young Healthy Persons Carrying the ApoE4 Allele Overexpress Stress-Related Proteins Involved in the Pathophysiology of Alzheimer's Disease

Article type: Research Article

Authors: Badia, Mari-Carmen^a | Lloret, Ana^b | Giraldo, Esther^b | Dasí, Francisco^b | Olaso, Gloria^b | Alonso, Maria-Dolores^c | Viña, Jose^{b; *}

Affiliations: [a] Department of Neurology, Hospital de Denia Marina Salud, Alicante, Spain | [b] Department of Physiology, Faculty of Medicine, University of Valencia, Valencia, Spain | [c] Department of Neurology, Hospital Clínico Universitario, Valencia, Spain

Correspondence: [*] Correspondence to: Prof. Jose Viña, Department of Physiology, Faculty of Medicine, University of Valencia, Avda. Blasco Ibañez 15, 46010 Valencia, Spain. Tel.: +34 96 3864650; Fax: +34 96 3864642; E-mail: [email protected].

Abstract: Apolipoprotein E4 (ApoE4) is a major genetic risk factor for the development of Alzheimer's disease (AD). The aim of this work was to find if carrying ApoE4 alleles correlates with molecular changes associated with specific processes involved in AD pathophysiology and whether they are useful as early biomarkers of AD. Fifty four young healthy adults (aged 20–55) were recruited. Of these, 33 carried at least one ApoE4 allele and 21 did not (ApoE 3/3). We also recruited eleven patients with clinical diagnoses of probable AD and nine persons of similar age without dementia who served as controls of the AD patients. Using peripheral lymphocytes, we measured RNA expression of glycogen synthase kinase 3β (GSK3β), the regulator of calcineurin 1 (RCAN1), calcineurin, and RNA-dependent protein kinase (PKR) by PCR and protein levels of RCAN1, calcineurin, GSK3β, and phospho-tau by western blotting. Young healthy persons carrying the ApoE 4/4 genotype express more RNA for RCAN1, calcineurin, and PKR and higher protein levels of calcineurin, RCAN1, GSK3β, and phospho-tau than controls (ApoE 3/3). Moreover, we found that carrying one or two alleles for ApoE4 is associated with subjective cognitive impairment. We conclude that lymphocytes from young, non-demented persons carrying the ApoE 4/4 genotype show molecular changes that are involved in specific processes associated with the pathophysiology of AD such as increased phosphorylation of tau or increased expression of stress-related proteins like calcineurin, GSK3β, or RCAN1. These changes may help to understand the development of AD and in the early diagnosis of the disease.

Keywords: Amyloid-β, calcineurin, GSK3β, RCAN1, tau

DOI: 10.3233/JAD-2012-120973

Journal: Journal of Alzheimer's Disease, vol. 33, no. 1, pp. 77-83, 2013