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.