Abstract
Alzheimer’s disease (AD) is a severe neurodegenerative disorder characterized mainly by accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic and neuronal loss. Blood platelets contain the neurotransmitter serotonin and amyloid-precursor protein (APP), and may thus be useful as a peripheral biomarker for AD. The aim of the present study was to functionally characterize platelets by FACS, to examine alterations in APP expression and secretion, and to measure serotonin levels in hypercholesterolemia mice with AD-like pathology and in two AD mouse models, the triple transgenic AD model (3xTg) and the APP overexpressing AD model with the Swedish–Dutch–Iowa mutations (APP_SweDI). These data are supplemented with epidermal growth factor (EGF) levels and compared with changes observed in platelets of patients with AD. We observed decreased platelet APP isoforms in 3xTg mice and patients with AD when analysed by means of Western blot. In patients, a significant increase of APP levels was observed when assessed by ELISA. Secreted APPβ proved to be altered amongst all three animal models of AD at different time points and in human patients with AD. Serotonin levels were only reduced in 7 and 14 month old 3xTg mice. Moreover, we found significantly lower EGF levels in human AD patients and could thereby reproduce previous findings. Taken together, our data confirm that platelets are dysfunctional in AD, however, results from AD animal models do not coincide in all aspects, and markedly differ when compared to AD patients. We support previous data that APP, as well as EGF, could become putative biomarkers for diagnosing AD in human platelets.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that gradually leads to severe cognitive deterioration and premature death
Values are given as mean ± SEM pg/ml 9 25 lg 9 150 min for secreted amyloid precursor protein beta (sAPPb), optical density (OD) for amyloid-precursor protein (APP) and ng/mg protein for serotonin
In the present study we assessed platelet APP, sAPPb and serotonin in three different mouse models and human patients with AD; we evaluated platelet epidermal growth factor (EGF) levels in our human cohort, in order to evaluate whether these components are altered in AD and whether platelets are useful as peripheral biomarkers in AD
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that gradually leads to severe cognitive deterioration and premature death. The diagnosis of possible or probable AD requires according to the current National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association (NINCDS–ADRDA) criteria both the presence of cognitive impairment established by clinical and neuropsychological examination and the absence of other diseases capable of producing a dementia syndrome, while definite AD diagnosis still requires post-mortem evaluation of plaques and NFTs in brain tissue (McKhann et al 1984; Dubois et al 2007). The diagnosis of AD within the clinical routine is based on a time consuming combination of psychological testing, imaging and the analysis of three well-established biomarkers (amyloid-b42 (Ab42), total tau and phospho-tau-181) in cerebrospinal fluid (CSF) (Blennow 2005; Blennow et al 2010; Zetterberg et al 2010; Tapiola et al 2009; Dubois et al 2007). We and others extensively searched for biomarkers in plasma/ serum (Blennow et al 2010; Ray et al 2007; Song et al 2009; Hu et al 2012; Chiu et al 2013), peripheral blood mononuclear cells (Hu et al 2014; Kassner et al 2008), monocytes (Hochstrasser et al 2012a; Naert and Rivest 2013; Shad et al 2013; Bradshaw et al 2013) or platelets (Adolfsson et al 1980; Di Luca et al 1996; Borroni et al 2010; Casoli et al 2010; Marksteiner and Humpel 2013)
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