Novel T719P AβPP Mutation Unbalances the Relative Proportion of Amyloid-β Peptides

Issue title: Mini-Forum: Roles of Amyloid-β and Tau Phosphorylation in Neuronal Repair and Protection

Guest editors: Garth Bissette

Article type: Research Article

Authors: Ghidoni, Roberta^{a; b; *} | Albertini, Valentina^a | Squitti, Rosanna^{c; d} | Paterlini, Anna^a | Bruno, Anna^b | Bernardini, Silvia^{d; e} | Cassetta, Emanuele^c | Rossini, Paolo Maria^{d; e} | Squitieri, Ferdinando^f | Benussi, Luisa^b | Binetti, Giuliano^b

Affiliations: [a] Proteomics Unit, IRCCS “Centro S. Giovanni di Dio-FBF”, Brescia, Italy | [b] NeuroBioGen Lab-Memory Clinic, IRCCS “Centro S. Giovanni di Dio-FBF”, Brescia, Italy | [c] Department of Neuroscience, AFaR-Ospedale Fatebenefratelli, Isola Tiberina, Rome, Italy | [d] Neurology, University Campus Biomedico, Rome, Italy | [e] Casa di Cura San Raffaele, Cassino & IRCCS San Raffaele Pisana, Rome, Italy | [f] Neurogenetics Unit, IRCCS Neuromed, Pozzilli (IS), Italy | Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA

Correspondence: [*] Corresponding author: Roberta Ghidoni, Proteomics Unit, NeuroBioGen Lab-Memory Clinic, IRCCS “Centro San Giovanni di Dio-Fatebenefratelli”, via Pilastroni 4, 25125 Brescia, Italy. Tel.: +39 030 3501725; Fax: +39 030 3533513; E-mail: [email protected].

Abstract: A novel missense mutation (T719P) in the amyloid-β protein precursor (AβPP) gene was discovered in a 46-year old patient affected by early onset familial Alzheimer's disease. Using surface enhanced laser desorption/ionization mass spectrometry (SELDI-TOF MS), we determined mass profiles of amyloid-β peptides (Aβ) in cerebrospinal fluid (CSF) of the AβPP mutated patient, healthy control subjects (n = 10), and of two subjects carrying mutations in presenilins genes (PS) (i.e., PS1 P117L and PS2 T122R): seven different C-terminally and three N-terminally truncated Aβ peptides were found in CSF. The investigated AβPP as well as PS mutations were associated with an overall reduction of Aβ species, except for Aβ10-40. Interestingly, the AβPP T719P mutation unbalanced the relative proportion of Aβ peptides with a reduction of Aβ1-40 and Aβ1-42 paralleled by an increase of Aβ1-38 and Aβ10-40. Despite the specific neuropeptidomic phenotype associated with the AβPP T719P mutation, the enrichment in Aβ10-40 paralleled by depletion of Aβ1-42 seems to be a common theme in familial AD. The AβPP T719P mutation is of particular interest because it is the only mutation located in close proximity to the AβPP ε-cleavage site.

Keywords: Amyloid-β protein precursor (AβPP) transmembrane domain, cleavage site at Aβ₄₈, ε-cleavage, familial Alzheimer's disease (FAD), γ-secretase, N- and C-terminally truncated amyloid-β peptides, presenilins, surface enhanced laser desorption/ionization mass spectrometry (SELDI-TOF MS)

DOI: 10.3233/JAD-2009-1142

Journal: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 295-303, 2009