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

Juan Pablo Palavicini,Linyuan Chen,Xianlin Han,Jianing Wang,Chunyan Wang,Takami Tomiyama,Hiroshi Mori,Kristen Hosang

doi:10.1186/s40478-017-0460-6

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.

Highlights

Decades of Alzheimer’s disease (AD) research have been grounded on the so called “amyloid cascade hypothesis”, which originally placed amyloid precursor protein (APP) mismetabolism and subsequent Amyloid beta (Aβ) aggregation as the initial trigger responsible for instigating further pathological events [49, 52, 97]
APP overexpression and oligomeric Aβ accumulation lead to significant and additive increases in unsaturated nonesterified fatty acids Analysis of nonesterified fatty acids (NEFAs, i.e., free Fatty acids (FA)) within cerebrum homogenates from old (24-month-old) mice revealed that both APP overexpression (APPWT) and oligomeric Aβ accumulation (APPOSK) lead to significant and additive increases of total Nonesterified fatty acids (NEFA) (24% and 57% increase, respectively) compared to non-Tg controls (Fig. 1a)
This increase occurred most dramatically within Polyunsaturated fatty acid (PUFA), which increased 1.7-fold in APPWT and 2.5-fold in APPOSK mouse brains compared to non-Tg controls

Summary

Introduction

Decades of Alzheimer’s disease (AD) research have been grounded on the so called “amyloid cascade hypothesis”, which originally placed amyloid precursor protein (APP) mismetabolism and subsequent Aβ aggregation (i.e., fibrillation) as the initial trigger responsible for instigating further pathological events (i.e., tauopathy, synaptic damage, and neuronal death) [49, 52, 97]. It has been shown that oligomeric Aβ species are both necessary and sufficient to disrupt cognitive function in vivo [21, 64, 107]. These findings led to a “revised” amyloid cascade hypothesis where diffusible oligomeric Aβ replaced fibrillar Aβ as the central neurotoxic event driving AD pathogenesis [48, 98]. APPOSK mice successfully recapitulate Aβ neurotoxicity in the absence of amyloid plaques

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Discussion

Conclusion