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LP226A1 in Alzheimer’s disease

The Central Nervous System (CNS) contains, after the adipose tissue, the greater amount of lipids in the body. Despite the tremendous amount of data indicating the relevance of lipids in the integrity and activity of neural networks, their roles have been consistently overlooked.

In this context, Alzheimer’s disease (AD) has been associated with decreases in the levels of DHA (docosahexaenoic acid) in CNS neuron membranes, which have been linked to the anomalous processing of the amyloid precursor protein (APP), resulting in production of beta-amiloid peptide (Abeta) and a cognitive decline (Martin et al., 2010; Lukiw & Bazan, 2008). This omega-3 lipid is the main polyunsaturated fatty acid in the brain and provides a great flexibility to neuron membranes. In fact, diets enriched in DHA slow AD and possibly other types of dementia (Cole et al., 2009; Cole & Frautschy, 2010).

 

LP226A1 is a potent dose-dependent inhibitor of Tau phosphorylation (both in vitro and in vivo) as determined in differentiated SH-SY5Y cells and in brain samples of transgenic 5xFAD mice with Familiar Alzheimer´s Disease). Treatment of 5xFAD mice with LP226A1 (15 mg/kg daily for 3 months) demonstrated a recovery of cognitive abilities as determined by a computer-assisted-radial maze exercise. This positive behavioural effect correlated with recovery of healthy brain biomarkers as restoration of neurogenesis and synaptic protein expression (synaptophysin and SNAP25) in the hippocampus. Concomitant with these effects a loss of the total brain Aβ amyloid load was observed. In addition, in vitro studies demonstrated the capacity of LP226A1 in restoring the viability of SH-SY5Y cells in cell culture intoxicated with Aβ amyloid peptide together with significant increases in markers of protective autophagy.

 

Relevant related documents:

::> The hydroxylated form of docosahexaenoic acid (DHA-H) modifies the brain lipid composition in a model of Alzheimer's disease, improving behavioral motor function and survival. Mohaibes RJ et al. Biochim Biophys Acta. 2017 Sep;1859(9 Pt B):1596-1603

 

icon Brain Lipids in the Pathophysiology and Treatment of Alzheimer’s Disease (5.02 MB). Torres M et al. Update on Dementia, Dr. Davide Moretti (Ed.), InTech, 2016. DOI: 10.5772/64757

 

::> The unfolded protein response in the therapeutic effect of hydroxy-DHA against Alzheimer’s disease. Torres M et al. Apoptosis. 2015 May

 

icon Membrane lipid modifications and therapeutic effects mediated by hydroxydocosahexaenoic acid on Alzheimers disease (1.18 MB) Torres et al. Biochim Biophys Acta. Jun. 2014

 

icon Cognitive recovery and restoration of cell proliferation in the dentate gyrus in the 5XFAD transgenic mice model of Alzheimer’s disease following 2-hydroxy-DHA treatment (742.35 kB) Fiol-deRoque et al. Gerontology. Oct. 2013


 

Proyecto financiado por el Ministerio de Economía y Competitividad y cofinanciado por los Fondos Europeos de Desarrollo Regional (FEDER)

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