SA34 - MITOCHONDRIAL DYSFUNCTION IN ALZHEIMER'S DISEASE

Abstract

Background Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive decline in memory and executive functions. APOE4 allele increases the risk for AD by 2.5 times in the Indian population. Previous reports show APOE4 is cleaved to produce toxic fragment, in neurons, which is associated with mitochondrial dysfunction. APOE4 is also associated with elevated mitochondria‐associated Endoplasmic Reticulum (ER) Membranes (MAM) dysfunction, similar to that of presenilin‐deficient cells. Further, an intronic poly T variant (L allele) of the TOMM40 gene (Translocase of Outer mitochondrial membrane) is reported to be associated with AD, and along with APOE4, seems to influence the age of onset in the disease (AAO). This poly T repeat acts as an enhancer, and influences the expression of both Tomm40 and APOE. Longer repeats are associated with increased expression of Tomm40 which in turn increases the reactive oxygen species production. Methods Subjects diagnosed with AD (n=167) at the clinical services of NIMHANS were invited to participate and provide blood samples after informed consent. Controls (n=179) were volunteers with no family or past history of neuro-psychiatric illness. APOE genotype was determined using allele specific primers. Mitochondrial DNA (mt DNA) copy number was estimated using SYBR Green. The relative copy number of mt DNA was assessed after ND1 and CytB normalization by a nuclear encoded housekeeping gene PK1.TOMM40 repeat length was estimated by polymerase chain reaction followed by fragment length analysis. Based on length the poly T polymorphism was divided into short allele (S 29). Results There is a significant association of APOE4 with AD (0.26) compared to controls (0.09). (p The mitochondrial DNA content was not significantly different between AD cases and age matched controls. However, APOE4 carriers showed significantly reduced mitochondrial DNA content than their non APOE4 counterpart. There was no significant correlation with age of onset or disease severity seen in the AD group. Discussion We explored the effect of the E4 allele on mitochondrial copy number, and find a diminished copy number in E4 carriers. Since the mitochondrial DNA copy number is known to affect expression of the mitochondrial genes, this might explain the changed bioenergetics in the context of AD. The L allele shows an increased allele frequency in APOE4 carriers. Further, AD cases that lack the APOE4 allele show presence of L allele. We conclude that the L allele of TOMM40 might have an additional role in pathogenicity in the AD context.