Cardiolipin Profile Changes are Associated to the Early Synaptic Mitochondrial Dysfunction in Alzheimer's Disease

Abstract

Brain mitochondria are fundamental to maintaining healthy functional brains, and their dysfunction is involved in age-related neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we conducted a research on how both non-synaptic and synaptic mitochondrial functions are compromised at an early stage of AD-like pathologies and their correlation with putative changes on membranes lipid profile, using 3 month-old nontransgenic and 3xTg-AD mice, a murine model of experimental AD. Bioenergetic dysfunction in 3xTg-AD brains is evidenced by a decrease of brain ATP levels resulting, essentially, from synaptic mitochondria functionality disruption as indicated by declined respiratory control ratio associated with a 50% decreased complex I activity. Lipidomics studies revealed that synaptic bioenergetic deficit of 3xTg-AD brains is accompanied by alterations in the phospholipid composition of synaptic mitochondrial membranes, detected either in phospholipid class distribution or in the phospholipids molecular profile. Globally, diacyl- and lyso-phosphatidylcholine lipids increase while ethanolamine plasmalogens and cardiolipins content drops in relation to nontransgenic background. However, the main lipidomic mark of 3xTg-AD brains is that cardiolipin cluster-organized profile is lost in synaptic mitochondria due to a decline of the most representative molecular species. In contrast to synaptic mitochondria, results support the idea that non-synaptic mitochondria function is preserved at the age of 3 months. Although the genetically construed 3xTg-AD mouse model does not represent the most prevalent form of AD in humans, the present study provides insights into the earliest biochemical events in AD brain, connecting specific lipidomic changes with synaptic bioenergetic deficit that may contribute to the progressive synapses loss and the neurodegenerative process that characterizes AD.

Aberrant cardiolipin metabolism is associated with cognitive deficiency and hippocampal alteration in tafazzin knockdown mice

“…Increasing evidence has implicated altered brain CL in the pathologic development of cognitive dysfunction in aging and multiple neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease 20,27,45,46 . However, a link between CL and cognitive impairment has not been clearly established.…”

Effect of high fat diet on phenotype, brain transcriptome and lipidome in Alzheimer’s model mice

“…Recently, it has been demonstrated that alterations of CL profile in brain of AD animal model are associated with synaptic mitochondrial dysfunction and oxidative stress 51 . In brain of HFD fed mice we identified 5 elevated CL molecular sub-species (68:4; 70;4; 72:4; 74:7; 84:20) and 2 (72:6; 76:11) with decreased amounts (Supplementary Table 1).…”

Influence of tissue, diet, and enzymatic remodeling on cardiolipin fatty acyl profile

“…Interestingly, however, cardiolipin in nonsynaptic mitochondria appears to be less resistant to aging‐mediated changes, undergoing a decrease in total content with advancing age, while the cardiolipin content of synaptic mitochondria remains well preserved . Conversely, in at least one model of Alzheimer's Disease, synaptic mitochondria are shown to undergo a decline in most cardiolipin species, while it is the non‐synaptic mitochondria that are well maintained .…”

“…Alterations in the cardiolipin content or composition of brain may have pathological consequences . Decreases in the total cardiolipin content of brain mitochondria have been reported in Parkinson's Disease , Alzheimer's Disease , and in age‐related dementia . Changes in the fatty acyl composition of brain cardiolipin are also reported.…”