Abstract
Alzheimer's disease (AD) is the most common cause of dementia. Amyloid plaques and neurofibrillary tangles are prominent pathological features of AD. Aging and age-dependent oxidative stress are the major nongenetic risk factors for AD. The beta-amyloid peptide (Aβ), the major component of plaques, and advanced glycation end products (AGEs) are key activators of plaque-associated cellular dysfunction. Aβ and AGEs bind to the receptor for AGEs (RAGE), which transmits the signal from RAGE via redox-sensitive pathways to nuclear factor kappa-B (NF-κB). RAGE-mediated signaling is an important contributor to neurodegeneration in AD. We will summarize the current knowledge and ongoing studies on RAGE function in AD. We will also present evidence for a novel pathway induced by RAGE in AD, which leads to the expression of thioredoxin interacting protein (TXNIP), providing further evidence that pharmacological inhibition of RAGE will promote neuroprotection by blocking neurovascular dysfunction in AD.
Highlights
Alzheimer’s disease (AD) pathology is characterized in by the presence of several kinds of amyloid plaques and neurofibrillary tangles in the brain, which are mainly composed by the beta amyloid (Aβ), derived from the proteolytic cleavage of the amyloid precursor protein (APP), and hyperphosphorylated tau [1]
Different animal models have been analyzed to decipher the role of receptor for AGEs (RAGE) in AD progression: (i) injection of advanced glycation end products (AGEs) into the rat hippocampus; (ii) injection of Aβ in rat hippocampus; (iii) various transgenic (Tg) mice expressing one or more gene variant of the amyloid precursor protein (APP); (iv) presenilins, which are implicated in APP cleavage and Aβ production leading to amyloid plaque formation; (v) tau that forms the characteristic tangles when is hyperphosphorylated
We summarize all studies indicating that RAGE participates in sporadic AD progression by activating several pathways in different cell types, blood brain barrier (BBB), glia, and neurons (Figure 4)
Summary
Alzheimer’s disease (AD) pathology is characterized in by the presence of several kinds of amyloid plaques and neurofibrillary tangles in the brain, which are mainly composed by the beta amyloid (Aβ), derived from the proteolytic cleavage of the amyloid precursor protein (APP), and hyperphosphorylated tau [1]. At early stages of AD, when the level of Aβ and AGEs are low, RAGE amplifies their effects on different cell types, contributing to neuronal dysfunction and neurodegeneration. Different animal models have been analyzed to decipher the role of RAGE in AD progression: (i) injection of AGEs into the rat hippocampus; (ii) injection of Aβ in rat hippocampus; (iii) various transgenic (Tg) mice expressing one or more gene variant of the amyloid precursor protein (APP); (iv) presenilins, which are implicated in APP cleavage and Aβ production leading to amyloid plaque formation; (v) tau that forms the characteristic tangles when is hyperphosphorylated. We recently demonstrated that RAGE triggering induces the expression of thioredoxin interacting protein (TXNIP) in various cell types, promoting inflammation [26, 27]. Inhibition of chronic activation of RAGE and TXNIP can efficiently provide neuroprotection in AD
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