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. For example, various types of sclerosis and neural dystrophies are associated with defects in the lipid layers of the neurons and Alzheimer’s disease and other neurodegenerative disorders are related to anomalous peptide depots (senile plaques) that overlay the plasma membrane of neurons.

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 polyunsaturated fatty acid derivative that was designed by Lipopharma with the aim of restoring the membrane lipid structure to prevent the molecular and cellular alterations observed in AD patients. The hypothesis used to rationally 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 plasma membrane structure must play a relevant role

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

 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 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. So far, we have determined a series of molecular events that could explain its capacity of prevent cognitive decline in AD animal models, including:

-> marked and significant reduction in the binding affinity of Abeta-42 to membranes.

-> strong capacity to inhibit gamma and beta secretase expression and activity, while no effect is observed on alpha secretase

-> inhibition of the total Abeta amyloid load and the beta-CTF (APP-C99 terminal fragment) in 7 months old 5xFAD mice after three months of treatment (total ABeta amyloid load mostly represent the insoluble form of Abeta present in senile plaques)

-> induction of the phosphorylation of GSK3Beta in 7 months old 5xFAD mice after three months of treatment, which could result in the inhibition of Tau phosphorylation

-> significant capacity of inducing neurogenesis in the hippocampus of 5XFAD mice

-> inhibition of AD-related neuroinflammatory responses

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.

Further studies to elucidate its Mechanism of Action (MOA) and to better determine its efficacy profile are currently under way.