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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 Aβamyloid peptide together with significant increases in markers of protective autophagy.

ptau

In vitro effect on phospho-Tau expression. Differentiated SH-SY5Y cells were treated during 24h with Aβ 42 peptide (5 μM) in the presence or absence of LP226A1 (5-30 μM)

 

 LP226A1 on secretases

Dose-dependent inhibition of PS1 (gamma) and BACE (beta) secretase expression by LP226A1 in differentiated SH-SY5Y neuroblastoma cells. No effect in alfa-secretase expression has been observed.

 

LP226A1 is a modified natural fatty acid with highly specific incorporation into neurons due to the specific omega-3 transporters present in neuronal membranes. Our data indicates that the main mechanism of action is the inhibition of Tau phosphorylation and as a consequence the normalization of a number of altered molecular markers of Alzheimer’s disease including the loss of Aβ amyloid load, activation of protective autophagy and synaptogenesis.

 

The hypothesis used to design and develop this compound is based on the fact that AD has a late onset and correlates with decline in membrane DHA. Therefore, in addition to mutations or other molecular events involved in progression of this condition, the membrane structure of neurons must play a relevant role

 

LP226A1, a synthetic derivative of DHA, has shown superior activity against neuronal death in cellular models.

 

LP226A1 in cells

Left: P-19 cell cultures were incubated in the presence of NMDA plus a number of potentially neuroprotective LP compounds. The bars correspond to mean ±SEM values of live neurons after 24-h incubations. Right: Dose-dependent effect of LP226A1 in inhibiting the toxic effect of extracellular Abeta in cultures of differentiated SHSY5Y neuroblastoma cells.

 

LP226A1 has also been investigated in an animal model (5XFAD mice) of Alzheimer’s disease (AD) where it shows significant disease modifying capacity and induces very important improvements in the scores of radial maze tests, preventing the development of Alzheimer’s disease in this animal model (see Figure below).

 

LP226A1 in mice

LP226A1. R.Mmaze

LP226A1 in the treatment of Alzheimer’s disease. The graphs show the number of errors (left) and time spent (right) to complete an exercise in the radial maze. For this purpose, healthy B6 mice were used as controls and a transgenic model of AD was used to test the efficacy of the compound (Alzh). Mice of 3 months of age were treated for 3 months with vehicle (water, p.o. once daily; Control and Alzh mice) or LP226A1 (once daily, p.o.). The scores in the radial maze were measured when the animals had an age of 6-7 months.

 

LP226A1 regulates the membrane lipid structure and composition of neurons and its molecular mechanisms of action are currently being investigated.

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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