Presynaptic Defects Underlying Impaired Learning and Memory Function in Lipoprotein Lipase-Deficient Mice

Abstract

Lipoprotein lipase (LPL) is predominantly expressed in adipose and muscle where it plays a crucial role in the metabolism of triglyceriderich plasma lipoproteins. LPL is also expressed in the brain with highest levels found in the pyramidal cells of the hippocampus, suggesting a possible role for LPL in the regulation of cognitive function. However, very little is currently known about the specific role of LPL in the brain. We have generated a mouse model of LPL deficiency which was rescued from neonatal lethality by somatic gene transfer. These mice show no exogenous and endogenous LPL expression in the brain. To study the role of LPL in learning and memory, the performance of LPL-deficient mice was tested in two cognitive tests. In a water maze test, LPL-deficient mice exhibited increased latency to escape platform and increased mistake frequency. Decreased latency to platform in the step-down inhibitory avoidance test was observed, consistent with impaired learning and memory in these mice. Transmission electron microscopy revealed a significant decrease in the number of presynaptic vesicles in the hippocampus of LPL-deficient mice. The levels of the presynaptic marker synaptophysin were also reduced in the hippocampus, whereas postsynaptic marker postsynaptic density protein 95 levels remained unchanged in LPL-deficient mice. Theses findings indicate that LPL plays an important role in learning and memory function possibly by influencing presynaptic function.

Do Low Serum UCH-L1 and TDP-43 Levels Indicate Disturbed Ubiquitin- Proteosome System in Autism Spectrum Disorder?

“…Altered ubiquitination resulting from abnormal UCH-L1 expression may contribute to learning and memory impairment (30). According to these aspects, mouse models in ASD, such as UBA6 brain-specific knockout mouse, suggest a relation of ubiquitination and autism.…”

SorLA regulates the activity of lipoprotein lipase by intracellular trafficking

“…Interestingly, we observed that a minor fraction of LPL was found in presynaptic vesicles but that it was absent from postsynaptic densities. LPL-deficient mice display impaired memory and this phenotype is attributed to a presynaptic defect in the hippocampus (Xian et al, 2009). Hence, it is tempting to speculate that SorLA regulates the routing of LPL to presynaptic vesicles and thereby affects general cognition.…”

“…In addition to adipose tissue and muscle, LPL expression is also detected in neurons and glia cells of the brain, with the highest levels found in the hippocampus (Xian et al, 2009). As SorLA is highly expressed throughout the brain, we speculated that SorLA might play an important role in the regulation of LPL activity in this tissue.…”

Lipoprotein lipase deficiency leads to α-synuclein aggregation and ubiquitin C-terminal hydrolase L1 reduction

“…LPL is highly expressed in hippocampal neurons (Eckel, 1989;Goldberg, 1996;Preiss-Landl et al, 2002), and involved in the pathogenesis of dementia (Vespa et al, 1999;Scacchi et al, 2004;Gong et al, 2013). Our lab first found that LPL deficient mice displayed memory impairment (Xian et al, 2009) and presynaptic dysfunction, which may due to impaired synaptic vesicle recycling (Liu et al, 2014). However, the exact mechanisms are still to be investigated.…”

“…Fig. 1A were also conducted in adult (12 months) LPL-deficient mice rescued from neonatal death by intramuscular injection of an adenoviral vector coding a human LPL mutant, Ad-LPLS447X, as previously described (Ross et al, 2005;Xian et al, 2009). All procedures were approved by the Animal Care Committee of Peking University Health Science Center in China.…”