Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: Increased susceptibility of females

Abstract

Apolipoprotein E (apoE) mediates the redistribution of lipids among cells and is expressed at highest levels in brain and liver. Human apoE exists in three major isoforms encoded by distinct alleles ( 2 , 3 , and 4 ). Compared with APOE 2 and 3 , APOE 4 increases the risk of cognitive impairments, lowers the age of onset of Alzheimer's disease (AD), and decreases the response to AD treatments. Besides age, inheritance of the APOE 4 allele is the most important known risk factor for the development of sporadic AD, the most common form of this illness. Although numerous hypotheses have been advanced, it remains unclear how APOE 4 might affect cognition and increase AD risk. To assess the effects of distinct human apoE isoforms on the brain, we have used the neuron-specific enolase (NSE) promoter to express human apoE3 or apoE4 at similar levels in neurons of transgenic mice lacking endogenous mouse apoE. Compared with NSE-apoE3 mice and wild-type controls, NSE-apoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and were seen primarily in females. These findings demonstrate that human apoE isoforms have differential effects on brain function in vivo and that the susceptibility to apoE4-induced deficits is critically influenced by age and gender. These results could be pertinent to cognitive impairments observed in human APOE 4 carriers. NSE-apoE mice and similar models may facilitate the preclinical assessment of treatments for apoErelated cognitive deficits.

Impairments in spatial memory retention of GFAP-apoE4 female mice

“…No cognitive impairments were seen in 10-13 month-old GFAP-apoE4 male mice in spatial learning and memory in the water maze [9]. Consistent with these data, no impairments in water maze performance were seen in 6 or 18-month-old apoE4 male mice expressing human apoE4 in neurons [17,18]. In contrast, 6-month-old female mice expressing apoE4 in neurons or astrocytes under control of the neuron specific enolase (NSE) or GFAP promoter, respectively, showed impairments in spatial memory retention in the probe trial following three day of hidden platform training in the water maze compared to sex-and age-matched Apoe −/− mice [17,18].…”

“…Apoe −/− mice had an average fall latency of 57.87 ± 4.84 sec, which was similar to that of GFAP-apoE3 mice (p = 0.4501) but not significantly different from apoE4 mice (p = 0.0746). In contrast to the comparable performance of 6-month-old GFAP-apoE3 and Apoe −/− female mice, 6-monthold NSE-apoE3 female mice performed better on the rotorod than Apoe −/− mice, reaching an average fall latency of 106 ± 19 sec versus 54 ± 7 sec (p < 0.05) [17]. These results indicate that the cell type expressing apoE is critically important in rotorod performance.…”

“…In contrast, 6-month-old female mice expressing apoE4 in neurons or astrocytes under control of the neuron specific enolase (NSE) or GFAP promoter, respectively, showed impairments in spatial memory retention in the probe trial following three day of hidden platform training in the water maze compared to sex-and age-matched Apoe −/− mice [17,18]. Such impairments were not seen in 6-month-old NSE-apoE3 female mice [14,[16][17][18]. The sex-dependency of the effects of apoE4 on cognitive function might involve androgen and androgen receptor-mediated signaling [15,16].…”

Role of H3-Receptor-Mediated Signaling in Anxiety and Cognition in Wild-Type and Apoe–/– Mice

“…Young (3-5 months old) Apoe -/-and wild-type mice were used in all the experiments, as indicated (n ¼ 5-19 mice per group). Young Apoe -/-mice were studied to evaluate a potential role of apoE on H 3 -receptor-mediated signaling, as adult Apoe -/-mice show age-dependent structural and functional alterations in the cortex and hippocampus (Masliah et al, 1995;Raber et al, 1998;Buttini et al, 1999). Such alterations could cause secondary changes in H 3 -receptor-mediated signaling.…”

Age-related accumulation of Reelin in amyloid-like deposits

“…The finding that recombinant ApoE ε3 and ε4 inhibit Reelin binding by 50 -60% (D'Arcangelo et al, 1999) indicates that lipid-associated ApoE could compete with Reelin for lipoprotein receptor activation. As a consequence, impaired ApoE receptor signaling may result in a dysbalance in cholesterol homeostasis, which has been shown to profoundly affect the production and trafficking of Aβ (Simons et al, 1998) and hypothesized to underlie accelerating synaptic loss and onset of dementia (Herz and Chen, 2006;Raber et al, 1998;Weeber et al, 2002). Further support for a direct link between Reelin and amyloid precursor protein (APP) processing has recently been proved by Hoe and colleagues by demonstrating that Reelin increases the intracellular interaction of Dab1 with ApoER2 and APP and promotes their cleavage, resulting in reduced toxic Aβ production (Hoe et al, 2006a).…”