The Genetic Variability of UCP4 Affects the Individual Susceptibility to Late-Onset Alzheimer’s Disease and Modifies the Disease’s Risk in APOE-ɛ4 Carriers

Article type: Research Article

Authors: Montesanto, Alberto^{a; 1} | Crocco, Paolina^{a; 1} | Anfossi, Maria^b | Smirne, Nicoletta^b | Puccio, Gianfranco^b | Colao, Rosanna^b | Maletta, Raffaele^b | Passarino, Giuseppe^a | Bruni, Amalia C.^b | Rose, Giuseppina^{a; *}

Affiliations: [a] Department of Biology, Ecology and Earth Science, University of Calabria, Rende (CS), Italy | [b] Regional Neurogenetic Centre, ASP CZ, Lamezia Terme (CZ), Italy

Correspondence: [*] Correspondence to: Giuseppina Rose, Department of Biology, Ecology and Earth Science, University of Calabria, 87036 Rende, Italy. Tel.: +39 0984492931; Fax: +39 0984493601; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Uncoupling proteins (UCPs) are a group of five mitochondrial inner membrane transporters with a tissue specific expression that uncouple biofuel oxidation from ATP synthesis and function as regulators of energy homeostasis and antioxidants. Previous data suggested that neuronal UCPs (UCP2, UCP4, and UCP5) can directly influence synaptic plasticity, neurotransmission, and neurodegenerative processes, and have a crucial role in the function and protection of the central nervous system. In fact, it has been observed that the expression of neuronal UCPs significantly decreases in Alzheimer’s disease (AD) patients. Here we analyzed the variability of UCP2, -3, -4, and 5 genes in sporadic and familial cases (n = 465) of late-onset AD (LOAD) with respect to healthy controls (n = 442). We showed that a genetic variant in the human UCP4, rs9472817, not only significantly affects the individual susceptibility to LOAD, but also modulates the effect of APOE-ɛ4 on AD risk. In fact, rs9472817-C allele was significantly more frequent in both groups of patients with respect to the control group (p = 6.934*10–4 for familial and p = 1.033*10–3 for sporadic cases). In addition, gene-gene interaction analysis revealed that the effect of APOE-ɛ4 allele on LOAD risk was doubled in homozygote CC subjects; conversely, the risk conferred by the APOE-ɛ4 allele was annulled in subjects with two copies of the G allele. Our findings are further evidence that the efficiency in mitochondrial energy metabolism and oxidative stress are important factors in AD pathogenesis.

Keywords: Alzheimer’s disease, APOE, genetic risk, mitochondria, neurodegeneration, UCP4, uncoupling proteins

DOI: 10.3233/JAD-150993

Journal: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1265-1274, 2016