Alzheimer's disease (AD) is characterized by the accumulation and deposition of amyloid-beta (Aβ) peptides in the brain. Neuroinflammation occurs in the AD brain and plays a critical role in the neurodegenerative pathology. Particularly, Aβ evokes an inflammatory response that leads to synaptic dysfunction, neuronal death, and neurodegeneration. Apolipoprotein E (ApoE) proteins are involved in cholesterol transport, Aβ binding and clearance, and synaptic functions in the brain. The ApoE4 isoform is a key risk factor for AD, while the ApoE2 isoform has a neuroprotective effect. However, studies have reached different conclusions about the roles of the isoforms; some show that both ApoE3 and ApoE4 have anti-infl ammatory effects, while others show that ApoE4 causes a predisposition to inflammation or promotes an inflammatory response following lipopolysaccharide treatment. These discrepancies may result from the differences in models, cell types, experimental conditions, and inflammatory stimuli used. Further, little was known about the role of ApoE isoforms in the Aβ-induced inflammatory response and in the neuroinflammation of AD. Our recent work showed that ApoE isoforms differentially regulate and modify the Aβ-induced infl ammatory response in neural cells, with ApoE2 suppressing and ApoE4 promoting the response. In this article, we review the roles, mechanisms, and interrelations among Aβ, ApoE, and neuroinfl ammation in AD.Keywords: ApoE; Alzheimer's disease; Aβ; neuroinfl ammation
IntroductionAlzheimer's disease (AD) is the leading cause of dementia in the elderly, and is a substantial burden on health-care systems worldwide. It is a neurodegenerative disease, characterized by progressive synaptic loss and neuronal death, and manifests over time as memory loss and cognitive decline. The severity increases with disease progression until the patient can no longer recognize family members or perform basic daily activities. In general, they eventually die from complications resulting from advanced debilitation. The majority of AD patients suffer from the sporadic late-onset form. Familial and early-onset forms exist as well, but their prevalence is much lower (<5%).
AD was initially described in 1906 by Alois Alzheimer uponexamining the brain of a 51-year-old woman who had died from early-onset dementia. His examination revealed two important features that still form the basis for pathological diagnosis: the build-up of intracellular neurofi brillary tangles (aggregates of hyperphosphorylated tau protein) and the formation of extracellular amyloid plaques (abnormal aggregates consisting principally of amyloid-beta (Aβ) peptides) [1] .
Alzheimer's Disease and Amyloid-betaAβ is a short peptide generated from β-amyloid precursor protein (APP) through two-step cleavage. The fi rst step is Neurosci Bull April 1, 2014, 30(2): 317-330 318 mediated by β-secretase or beta-site APP cleaving enzyme 1 (BACE1), which produces a large soluble protein and a 99-amino-acid membrane-bound C-terminal stub (C99).The C99 fragme...
