Structural lipid deficits and cholinergic function The cholinergic hypothesis of cognitive dysfunction in AD remains a core concept in AD research [59]. Understanding the pathophysiology of this neurotransmitter deficit is at the core of many research group’s e orts in defining potential new therapeutic approaches for AD. Based upon our current knowledge of lipidomics changes in Nutlin-3a Mdm2 the AD brain, the following points can be summarized about the possible negative contributions of lipid deficits on cholinergic function. First, decrements in sulfatides and plasmalogens, resulting in hypomyelination and membrane dysfunction, may be responsible for the marked shrinkage of nucleus basalis-cortical cholinergic neurons [57-59]. Second, hypomyelination is known to reduce axonal transport in AD cortex [61].

Decreased anterograde transport of choline acetyltransferase and the acetylcholine vesicular transporter would reduce the synthetic and storage capacities for acetylcholine in the cortical nerve terminal fields [59]. Decreased retrograde transport of essential trophic factors from the cortex to the cholinergic cell bodies in the basal forebrain would lead to decreased trophic support and decreased cell body synthesis of critical proteins required for cholinergic neuronal function [59]. Third, decreased availability of plasmalogens to cholinergic nerve terminal would impact mitochondrial function and neurotransmitter vesicular fusion with the presynaptic membrane, both resulting in decreased synaptic acetylcholine release [59]. Accumulation of VLCFAs [15] also will negatively affect mitochondrial function.

Fourth, decreased plasmalogens in AD membrane lipid rafts [62] would alter membrane fluidity uncoupling cholinergic muscarinic receptors in AD cortex [63], as has been shown to occur in plasmalogen-deficient cell lines [64]. Decreased acetylcholine release coupled with impaired postsynaptic signal Batimastat transduction may well be responsible selleck Dovitinib for the marked cholinergic deficit in AD patients [59]. Fifth, deficits in sulfatides and plasmalogens also will negatively affect gap junction integrity, thereby impairing glial metabolic support of cholinergic nerve terminals in the cortex [59]. Sixth, decreases in membrane plasmalogen levels result in decreased export of cholesterol, further contributing to membrane rigidity [59,65]. This increase in membrane rigidity is hypothesized to contribute to abnormal processing of ??-amyloid in AD [59,65]. Seventh, neuroinflammation is a hallmark feature of AD brain [38,59]. In this regard, neuroinflammation has been demonstrated to be induced by metabolites of sphingolipids and by decrements in membrane plasmalogens, both features of AD brain [59].