Autosomal‐dominant Alzheimer's disease mutations at the same codon of amyloid precursor protein differentially alter Aβ production. (24th October 2013)

• Record Type: Journal Article
• Authors: Suárez‐Calvet, Marc; Belbin, Olivia; Pera, Marta; Badiola, Nahuai; Magrané, Jordi; Guardia‐Laguarta, Cristina; Muñoz, Laia; Colom‐Cadena, Martí; Clarimón, Jordi; Lleó, Alberto
• Is Part Of: Journal of neurochemistry. Volume 128:Number 2(2014:Jan.)
• Page Start: 330
• Page End: 339
• Publication Date: 2013-10-24
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.12466
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc12466-abs-0001"> <title>Abstract</title> <p>Autosomal‐dominant Alzheimer's disease (ADAD) is a genetic disorder caused by mutations in <italic>Amyloid Precursor Protein</italic> (<italic>APP</italic>) or <italic>Presenilin</italic> (<italic>PSEN</italic>) genes. Studying the mechanisms underlying these mutations can provide insight into the pathways that lead to AD pathology. The majority of biochemical studies on <italic>APP</italic> mutations to‐date have focused on comparing mechanisms between mutations at different codons. It has been assumed that amino acid position is a major determinant of protein dysfunction and clinical phenotype. However, the differential effect of mutations at the same codon has not been sufficiently addressed. In the present study we compared the effects of the aggressive ADAD‐associated <italic>APP</italic> I716F mutation with I716V and I716T on APP processing in human neuroglioma and CHO‐K1 cells. All <italic>APP</italic> I716 mutations increased the ratio of Aβ42/40 and changed the product line preference of γ‐secretase towards Aβ38 production. In addition, the <italic>APP</italic> I716F mutation impaired the ε‐cleavage and the fourth cleavage of γ‐secretase and led to abnormal APP β‐CTF accumulation at the plasma membrane. Taken together, these data indicate that <italic>APP</italic> mutations at the same codon can induce diverse abnormalities in APP processing, some resembling <italic>PSEN1</italic> mutations. These differential effects could explain the clinical differences observed among ADAD patients bearing different <italic>APP</italic> mutations at the same position. <boxed-text content-type="graphic" id="jnc12466-blkfxd-0001" position="anchor" orientation="portrait"><graphic position="anchor" mimetype="image" xlink:href="ark:/27927/pgg3zxq00rc" orientation="portrait" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /></boxed-text></p> <p>The amyloid precursor protein (<italic>APP</italic>) I716F mutation is associated with autosomal dominant Alzheimer's disease with the youngest age‐at‐onset for the APP locus. Here, we describe that this mutation, when compared to two other familial Alzheimer's disease mutations at the same codon (I716V and I716T), interfered distinctly with γ‐secretase cleavage. While all three mutations direct γ‐secretase cleavage towards the 48→38 production line, the APP I716F mutation also impaired the ε‐cleavage and the fourth cleavage of γ‐secretase, resembling a <italic>PSEN1</italic> mutation. These features may contribute to the aggressiveness of this mutation.</p> </abstract>