Brain Lipids in the Pathophysiology and Treatment of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that causes severe and progressive cognitive impairment. The discovery of specific mutations related to AD supported the amyloid cascade hypothesis, which postulates that the accumulation of the amyloid-β (Aβ) peptide triggers neuronal death and dementia. However, most drugs that aim to prevent Aβ accumulation or tau phosphorylation have consistently failed in clinical trials. This would suggest that the amyloid pathology lies downstream of (an)other cellular event(s) that is/are responsible for AD pathogenesis. In this context, several lipid alterations have been described in the brain and in peripheral fluids of patients with AD, suggesting the involvement of lipids in the etiology of this condition. Indeed, the central nervous system (CNS) has the highest lipid content in the body, next to adipose tissue, and it is thought that normalization of brain membrane lipid levels would revert AD-related pathogenic events. In this sense, novel hydroxylated derivatives of docosahexaenoic acid (DHA) such as natural resolvins or synthetic hydroxy-DHA (HDHA, DHALifort) can modulate membrane lipid composition and show remarkable beneficial effects on AD hallmarks, such as prevention of amyloid production and tau phosphorylation, and cognitive restoration in animal models. Therefore, normalization of the neuronal lipid environment by hydroxyl-DHA and/or other lipids may constitute a promising therapy for AD treatment, memory loss and, possibly, other types of dementia.

Proteomic and Biological Profiling of Extracellular Vesicles from Alzheimer’s Disease Human Brain Tissues

“…First, cholesterol level might be related to EV size; the CNS is known to contain 25% of the body's cholesterol and accumulation of cholesterol is reported to be associated with AD [37].…”

“…High cholesterol levels increase Aβ in cellular and animal models of AD, and the chemical that inhibits cholesterol synthesis reduces Aβ in this model [37][38][39][40][41]. Moreover, it has been reported that small EVs contain significantly higher cholesterol than do large EVs [38,39].…”

Label-free characterization of Amyloid-β-plaques and associated lipids in brain tissues using stimulated Raman scattering microscopy

“…(ii) the neuritic dystrophy hypothesis proposes that plaque-associated lipids may originate from the degeneration of neurites and myelin sheaths in AD 36 . And, (iii) the immune system hypothesis suggests that plaque-associated lipids may originate from interactions of the brain's innate immune system with pathological Aβ aggregates 37,38,39 .…”

2-Hydroxy-Docosahexaenoic Acid Is Converted Into Heneicosapentaenoic Acid via α-Oxidation: Implications for Alzheimer’s Disease Therapy

“…Both these neuropathological features have long been considered to be the molecular events triggering AD-related pathophysiological events, in accordance with the amyloid cascade hypothesis (Selkoe and Hardy, 2016). However, this concept is challenged by the fiascos of clinical trials with antiamyloid/tau therapies to date (Krstic and Knuesel, 2013;Herrup, 2015;Torres et al, 2016;Ricciarelli and Fedele, 2017). In this context, AD has been associated with several lipid alterations that are related to neurodegeneration, such as hypercholesterolemia (Martins et al, 2009), alterations in sphingomyelin storage (Tamboli et al, 2011), and a downregulation of docosahexaenoic acid (DHA) and related bioactive hydroxylated mediators like NPD1 (Neuroprotectin D1) (Prasad et al, 1998;Lukiw et al, 2005;Astarita et al, 2010).…”

“…The Disease Modifying Drugs (DMDs) designed and tested in clinical trials have reported adverse effects and/or no clinical improvement. Most of these DMDs are drugs or biological agents (immunotherapy) designed to inhibit or modulate the amyloid pathology and/or tauopathy evident in AD (Torres et al, 2016). Both these neuropathological features have long been considered to be the molecular events triggering AD-related pathophysiological events, in accordance with the amyloid cascade hypothesis (Selkoe and Hardy, 2016).…”