STUDYING THE ROLE OF ApoE IN ALZHEIMER'S DISEASE PATHOGENESIS USING A SYSTEMS BIOLOGY MODEL

Abstract

Alzheimer's disease (AD) is the most common form of dementia. Even with its well-known symptoms of memory loss and well-characterized pathology of beta amyloid (Aβ) plaques and neurofibrillary tangles, the disease pathogenesis and initiating factors are still not well understood. To tackle this problem, a systems biology model has been developed and used to study the varying effects of variations in the ApoE allele present, as well as the effects of short term and periodic inflammation at low to moderate levels. Simulations showed a late onset peak of Aβ in the ApoE4 case that lead to localized neuron loss which could be ameliorated in part by application of short-term pro-inflammatory mediators. The model that has been developed herein represents one of the first attempts to model AD from a systems approach to study physiologically relevant parameters that may prove useful to physicians in the future.

The Impact of Mathematical Modeling in Understanding the Mechanisms Underlying Neurodegeneration: Evolving Dimensions and Future Directions

“…The mechanism of formation of Aβ fibrils has been modelled by several groups: Kinetics of Aβ aggregation has been described using mathematical models 12, 13, 14, 39, 54, 55.Activated microglia increases the production of Aβ through the secretion of Interleukin‐1 (IL‐1) whilst quiescent microglia helps to maintain Aβ production within a healthy range. Neuroinflammation associated with AD has been quantitatively investigated 41.…”

“…Increasing evidence is emerging about the role of genetic factors, such as apolipoprotein E (ApoE) allele variation, in the disease pathology. The interplay between the effects of variations in the ApoE allele and the inflammation dynamics in AD has been studied using a mathematical model, which suggests that a late onset peak of Aβ in the ApoE4 case lead to localized neuronal loss, which could be improved by application of short‐term proinflammatory mediators 39. Chronic activation of the brain immune cell, microglia, is believed to impair survival‐related processes leading to decreased protein synthesis and cellular energy, which affect neurotransmitter concentrations and neuronal activity in general.…”

“…The interplay between the effects of variations in the ApoE allele and the inflammation dynamics in AD has been studied using a mathematical model, which suggests that a late onset peak of Ab in the ApoE4 case lead to localized neuronal loss, which could be improved by application of short-term proinflammatory mediators. 39 Chronic activation of the brain immune cell, microglia, is believed to impair survival-related processes leading to decreased protein synthesis and cellular energy, which affect neurotransmitter concentrations and neuronal activity in general. Dunster et al 40 developed a mathematical model to understand the inflammatory process by studying the crosstalk between neutrophils and macrophages.…”

“…• Cholesterol is shown to inhibit b-secretase activity thereby decreasing the production of Ab. The role of cholesterol on amyloidogenic processing has been investigated 39 . • A decrease in acetylcholine (ACh) concentration causes an increase in the synthesis of APP and favours the processing of APP by the b-pathway 66,67 .…”

Atomistic Insights into Structural Differences between E3 and E4 Isoforms of Apolipoprotein E

“…One of the most common forms of dementia is Alzheimer's disease (AD) (1), characterized by the formation of neurofibrillary tangles and plaques in the brain, leading to neuronal dysfunction, neuronal loss, and finally, death. The increased risk of developing AD is associated with the Apolipoprotein E (ApoE) gene (2)(3)(4), which is located on the long arm of chromosome 19 (5).…”