BACE1 RNAi Restores the Composition of Phosphatidylethanolamine-Derivates Related to Memory Improvement in Aged 3xTg-AD Mice

Abstract

β-amyloid (Aβ) is produced by the β-secretase 1 (BACE1)-mediated enzymatic cleavage of the amyloid precursor protein through the amyloidogenic pathway, making BACE1 a therapeutic target against Alzheimer’s disease (AD). Alterations in lipid metabolism are a risk factor for AD by an unknown mechanism. The objective of this study was to determine the effect of RNA interference against BACE1 (shBACEmiR) on the phospholipid profile in hippocampal CA1 area in aged 3xTg-AD mice after 6 and 12 months of treatment compared to aged PS1KI mice. The shBACEmiR treatment induced cognitive function recovery and restored mainly the fatty acid composition of lysophosphatidylethanolamine and etherphosphatidylethanolamine, reduced the cPLA2’s phosphorylation, down-regulated the levels of arachidonic acid and COX2 in the hippocampi of 3xTg-AD mice. Together, our findings suggest, for the first time, that BACE1 silencing restores phospholipids composition which could favor the recovery of cellular homeostasis and cognitive function in the hippocampus of triple transgenic AD mice.

Evaluation of BACE1 silencing as a therapy against Alzheimer disease: implications for lipid metabolism and inflammatory response

“…1A). These observations were supported by our previous studies, which demonstrated that BACE1 RNAi (BACE1-KD) reduces BACE1 protein levels in both primary neuronal cultures and the injected brain region of an Alzheimer´s mice model by approximately 50% (D Piedrahita, Castro-Alvarez, Villamil-Ortiz et al 2016). Glutamate (125 µM) increased hyperphosphorylated tau (AT8) levels in the shSCRmiR (control) group (p<0.0001) (Fig.…”

“…Inhibition of this enzyme has been viewed as an Aβ-lowering therapeutic intervention, but several problems have prevented BACE1 inhibitors from advancing to pivotal clinical trials, especially because BACE1 has multiple functional subunits ). However, we and others have found that BACE1 targeting improves longterm spatial memory and prevents Aβ plaques and tau aggregation Sierant et al 2009;Villamil-Ortiz et al 2016), with a reduction of 50% compared to the upregulated condition in neurodegeneration ).…”

“…General Introduction gamma-secretase inhibitors, aggregation blockers, vaccination with Aβ, vaccination with monoclonal antibodies against Aβ epitopes are ongoing. Finally, other candidates have been proposed for their potential as a therapy, such as genetic therapies by neutralizing targeted mRNA molecules of β or Ω secretase, however, they are still in development stages (Diego Piedrahita et al 2016;Villamil-Ortiz et al 2016).…”

Activation of peroxisome proliferator‐activated receptor delta suppresses BACE1 expression by up‐regulating SOCS1 in a JAK2/STAT1‐dependent manner

“…Decreased expression and activity of BACE1 reduces progressive deposition of Aβ and is associated with synaptic pathology in animal and cell‐based models of AD (Villamil‐Ortiz et al . ; Peters et al . ).…”

Dementia, Preclinical Studies in Neurodegeneration and its Potential for Translational Medicine in South America

“…These deficits in long-term synaptic plasticity correlate with the accumulation of intraneuronal βA and NTFs formation. Interestingly, silenced BACE1 (main enzyme involved in the production of βA), in the hippocampus using adenoassociated viral vectors reduces the hyperphosphorilation of tau (Piedrahita et al, 2016) and improve cognitive function at 6 months and 12 months post-treatment, presenting a balanced phospholipid composition, by the reduction of saturated fatty acid (stearic acid (18:0), palmitic acid (16:0)) and increase of poli-unsaturated fatty acid (docosahexaenoic acid, DHA (22:6)), which prevented the activation of pro-inflammatory signaling cPLA2/AA/COX2 in old AD mice to long-term post-therapy (Villamil-Ortiz et al, 2016). Also, the silencing of CDK5 in the CA1 hippocampal area prevents the spreading of excitoxicity to other areas of the neuronal circuit (Piedrahita et al, 2010; Castro-Alvarez et al, 2014, 2015; Posada-Duque et al, 2015a) also reversing (Piedrahita et al, 2010) or preventing neurodegeneration by reduction of paired helicoidal formations (Castro-Alvarez et al, 2014) and further, decreases the β amyloidosis production (Castro-Alvarez et al, 2015).…”