Oligomeric amyloid-beta induces MAPK-mediated activation of brain cytosolic and calcium-independent phospholipase A2 in a spatial-specific manner

Abstract

Alzheimer’s disease (AD) is histopathologically characterized by the build-up of fibrillar amyloid beta (Aβ) in the form of amyloid plaques and the development of intraneuronal neurofibrillary tangles consisting of aggregated hyperphosphorylated Tau. Although amyloid fibrils were originally considered responsible for AD pathogenesis, recent convincing evidence strongly implicates soluble oligomeric Aβ as the primary neurotoxic species driving disease progression. A third largely ignored pathological hallmark, originally described by Alois Alzheimer, is the presence of “adipose inclusions”, suggestive of aberrant lipid metabolism. The molecular mechanisms underlying these “lipoid granules”, as well as their potential link to soluble and/or fibrillar Aβ remain largely unknown. Seeking to better-understand these conundrums, we took advantage of the powerful technology of multidimensional mass spectrometry-based shotgun lipidomics and an AD transgenic mouse model overexpressing mutant amyloid precursor protein (APP E693Δ-Osaka-), where AD-like pathology and neurodegeneration occur as a consequence of oligomeric Aβ accumulation in the absence of amyloid plaques. Our results revealed for the first time that APP overexpression and oligomeric Aβ accumulation lead to an additive global accumulation of nonesterified polyunsaturated fatty acids (PUFAs) independently of amyloid plaques. Furthermore, we revealed that this accumulation is mediated by an increase in phospholipase A2 (PLA2) activity, evidenced by an accumulation of sn-1 lysophosphatidylcholine and by MAPK-mediated phosphorylation/activation of group IV Ca2+-dependent cytosolic (cPLA2) and the group VI Ca2+-independent PLA2 (iPLA2) independently of PKC. We further revealed that Aβ-induced oxidative stress also disrupts lipid metabolism via reactive oxygen species-mediated phospholipid cleavage leading to increased sn-2 lysophosphatidylcholine as well as lipid peroxidation and the subsequent accumulation of 4-hydroxynonenal. Brain histological studies implicated cPLA2 activity with arachidonic acid accumulation within myelin-rich regions, and iPLA2 activity with docosahexaenoic acid accumulation within pyramidal neuron-rich regions. Taken together, our results suggest that PLA2-mediated accumulation of free PUFAs drives AD-related disruption of brain lipid metabolism.

Early disruption of nerve mitochondrial and myelin lipid homeostasis in obesity-induced diabetes

“…MALDI MS imaging. MALDI MS imaging of sulfatide and major phospholipids was carried out as previously described (80)(81)(82). Briefly, fresh frozen brains from C57BL/6 J WT and db/db mice were cryosectioned sagittally at a width of 10 μm using a Leica CM1900 cryostat (Leica Biosystems) at -12°C (chamber temperature).…”

“…PNS and CNS tissues were homogenized in 1× NP-40. Western blotting was performed using NP-40 supernatants as previously described (81). Antibodies used in this study are detailed in Supplemental Table 2.…”

The phospholipase A2 pathway controls a synaptic cholesterol ester cycle and synapse damage

“…1C). Because Aβ activates cPLA 2 (Palavicini et al, 2017;Zhu et al, 2006), we sought to determine whether activated cPLA 2 was involved in the increased synaptic cholesterol concentrations by using two selective cPLA 2 inhibitors [arachidonyl trifluoromethyl ketone (AACOCF 3 ) and methyl arachidonyl fluorophosphonate (MAFP)]. The activation of cPLA 2 is the first step in the production of bioactive lipids [including prostaglandins (PGs) and PAF] that affect synapse function (Clark et al, 1992;Sang et al, 2005).…”

APP Osaka Mutation in Familial Alzheimer’s Disease—Its Discovery, Phenotypes, and Mechanism of Recessive Inheritance

“…Finally, the Osaka mutation provides a useful means to investigate the pathological and physiological roles of Aβ oligomers without the influence of amyloid fibrils or plaques (for example, [75][76][77][78]). Additionally, our model mice harboring this mutation could be a good tool for developing effective approaches in the prevention, treatment, and diagnosis of AD that specifically target Aβ oligomers (for example, [79,80]).…”