Alzheimer’s disease (AD) is the leading cause of dementia worldwide. The extracellular deposits of Amyloid beta (Aβ) in the brain—called amyloid plaques, and neurofibrillary tangles—intracellular tau aggregates, are morphological hallmarks of the disease. The risk for AD is a complicated interplay between aging, genetic risk factors, and environmental influences. One of the Apolipoprotein E (APOE) alleles—APOEε4, is the major genetic risk factor for late-onset AD (LOAD). APOE is the primary cholesterol carrier in the brain, and plays an essential role in lipid trafficking, cholesterol homeostasis, and synaptic stability. Recent genome-wide association studies (GWAS) have identified other candidate LOAD risk loci, as well. One of those is the triggering receptor expressed on myeloid cells 2 (TREM2), which, in the brain, is expressed primarily by microglia. While the function of TREM2 is not fully understood, it promotes microglia survival, proliferation, and phagocytosis, making it important for cell viability and normal immune functions in the brain. Emerging evidence from protein binding assays suggests that APOE binds to TREM2 and APOE-containing lipoproteins in the brain as well as periphery, and are putative ligands for TREM2, thus raising the possibility of an APOE-TREM2 interaction modulating different aspects of AD pathology, potentially in an isoform-specific manner. This review is focusing on the interplay between APOE isoforms and TREM2 in association with AD pathology.

High-fat diet and certain dietary patterns are associated with higher incidence of sporadic Alzheimer's disease (AD) and cognitive decline. However, no specific therapy has been suggested to ameliorate the negative effects of high fat/high cholesterol levels on cognition and amyloid pathology. Here we show that in 9-month-old APP23 mice, a high-fat/high-cholesterol (HF) diet provided for 4 months exacerbates the AD phenotype evaluated by behavioral, morphological, and biochemical assays. To examine the therapeutic potential of liver X receptor (LXR) ligands, APP23 mice were fed HF diet supplemented with synthetic LXR agonist T0901317 (T0). Our results demonstrate that LXR ligand treatment causes a significant reduction of memory deficits observed during both acquisition and retention phases of the Morris water maze. Moreover, the effects of T0 on cognition correlate with AD-like morphological and biochemical parameters. We found a significant decrease in amyloid plaque load, insoluble Aβ and soluble Aβ oligomers.In vitroexperiments with primary glia demonstrate that Abca1 is essential for the proper lipidation of ApoE and mediates the effects of T0 on Aβ degradation by microglia. Microdialysis experiments performed on awake freely moving mice showed that T0 decreased Aβ levels in the interstitial fluid of the hippocampus, supporting the conclusion that this treatment increases Aβ clearance. The data presented conclusively shows that LXR activation in the context of a metabolic challenge has critical effects on AD phenotype progression by attenuating Aβ deposition and facilitating its clearance.

Cramer et al . (Reports, 23 March 2012, p. 1503; published online 9 February 2012) demonstrated in a mouse model for Alzheimer’s disease (AD) that treatment of APP/PS1ΔE9 mice with bexarotene decreased Aβ pathology and ameliorated memory deficits. We confirm the reversal of memory deficits in APP/PS1ΔE9 mice expressing human APOE3 or APOE4 to the levels of their nontransgenic controls and the significant decrease of interstitial fluid Aβ, but not the effects on amyloid deposition.

ATP-binding cassette transporter A1 (ABCA1) transporter regulates cholesterol efflux and is an essential mediator of high-density lipoprotein (HDL) formation. In amyloid precursor protein (APP) transgenic mice,Abca1deficiency increased amyloid deposition in the brain paralleled by decreased levels of Apolipoprotein E (ApoE). TheAPOEε4allele is the major genetic risk factor of sporadic Alzheimer's disease (AD). Here, we reveal the effect ofAbca1deficiency on phenotype in mice expressing human ApoE3 or ApoE4. We used APP/E3 and APP/E4 mice generated by crossing APP/PS1ΔE9 transgenic mice to human APOE3- and APOE4-targeted replacement mice and examinedAbca1gene dose effect on amyloid deposition and cognition. The results from two behavior tests demonstrate that lack of one copy ofAbca1significantly exacerbates memory deficits in APP/E4/Abca1^−/+but not in APP/E3/Abca1^−/+mice. The data for amyloid plaques and insoluble amyloid-β (Aβ) also show thatAbca1hemizygosity increases Aβ deposition only in APP/E4/Abca1^−/+but not in APP/E3/Abca1^−/+mice. Ourin vivomicrodialysis assays indicate thatAbca1deficiency significantly decreases Aβ clearance in ApoE4-expressing mice, while the effect ofAbca1on Aβ clearance in ApoE3-expressing mice was insignificant. In addition, we demonstrate that plasma HDL and Aβ42 levels in APP/E4/Abca1^−/+mice are significantly decreased, and there is a negative correlation between plasma HDL and amyloid plaques in brain, suggesting that plasma lipoproteins may be involved in Aβ clearance. Overall, our results prove that the presence of functionalAbca1significantly influences the phenotype of APP mice expressing human ApoE4 and further substantiate therapeutic approaches in AD based on ABCA1–APOE regulatory axis.