ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?

Abstract

Among the three human apolipoprotein E (apoE) isoforms, apoE4 increases the risk of Alzheimer’s disease (AD). While transporting cholesterol is a primary function, apoE also regulates amyloid-β (Aβ) metabolism, aggregation and deposition. Although earlier work suggests that different affinities of apoE isoforms to Aβ might account for their effects on Aβ clearance, recent studies indicate that apoE also competes with Aβ for cellular uptake through apoE receptors. Thus, several factors likely determine the variable effects apoE has on Aβ. In this review, we examine biochemical, structural, and functional studies and propose testable models that address the complex mechanisms underlying apoE-Aβ interaction and how apoE4 may increase AD risk and also serve as a target pathway for therapy.

Metabolic Profiling and Phenotyping of Central Nervous System Diseases: Metabolites Bring Insights into Brain Dysfunctions

“…The authors identified a metabolic signature of ten plasmatic lipids that were predictive of the occurrence of mild cognitive impairment or Alzheimer's disease within a 2-3 year timeframe with over 90% accuracy. These data support the involvement of dyslipidemia in AD and are in line with the abundant literature on the APOE4 variant as a major risk allele for AD that leads to disruption in sterol and sphingolipid metabolism (Kanekiyo et al 2014). …”

“…One study even showed that sphingomyelins and ceramides species levels correlated with cognitive performance in AD patients (Han et al 2011). More recently, a study profiled the plasma lipid profile of a cohort of cognitively normal elderly adults and followed the same individuals four years, at a time by which some individuals had developed AD (Kanekiyo et al 2014). The authors identified a metabolic signature of ten plasmatic lipids that were predictive of the occurrence of mild cognitive impairment or Alzheimer's disease within a 2-3 year timeframe with over 90% accuracy.…”

Apolipoprotein E Inhibits Cerebrovascular Pericyte Mobility through a RhoA Protein-mediated Pathway

“…In addition, apoE also directly regulates cellular functions, including the modulation of inflammatory response (3,4), cell migration, and proliferation (5,6). Humans have three polymorphic APOE alleles (⑀2, ⑀3, and ⑀4).…”

“…The most common allele found in the general population is ⑀3, followed by ⑀4 and, finally, ⑀2 (2,4,7). Growing evidence has shown that APOE ⑀4 carriers are at increased risk for age-related cognitive decline during normal aging as well as Alzheimer disease (2,4,7). Furthermore, APOE4 is also shown as an anti-longevity gene by disturbing lipid metabolism (8).…”

“…ApoE derived from astrocytes is a major apolipoprotein present in the brain, exhibiting a primary function in lipid transport and supporting synapses and dendritic spines (2,4,7). However, information on the biochemical properties and functions of apoE produced by other cell types in the brain is limited.…”