%0 Journal Article
%T The Complexity of Sporadic Alzheimer¡¯s Disease Pathogenesis: The Role of RAGE as Therapeutic Target to Promote Neuroprotection by Inhibiting Neurovascular Dysfunction
%A Lorena Perrone
%A Oualid Sbai
%A Peter P. Nawroth
%A Angelika Bierhaus
%J International Journal of Alzheimer's Disease
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/734956
%X 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 (A¦Â), the major component of plaques, and advanced glycation end products (AGEs) are key activators of plaque-associated cellular dysfunction. A¦Â 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-¦ÊB). 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. 1. Introduction 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 (A¦Â), derived from the proteolytic cleavage of the amyloid precursor protein (APP), and hyperphosphorylated tau [1]. AD can be subdivided in 2 major forms: (i) familial AD, which represents rare early onset forms due to gene mutations leading to enhanced A¦Â production or faster aggregating A¦Â peptide; (ii) sporadic AD forms, which represent about 95% of AD cases [2]. The pathogenesis of sporadic AD is extremely complex, and its ultimate cause is still under debate. Epidemiological studies reveal growing evidence that most cases of sporadic AD likely involve a combination of genetic and environmental risk factors. However, the only risk factors so far validated for late-onset disease are age, family history, and the susceptibility gene ApoE4 allele [3]. A hallmark of the aged brain is the presence of oxidative stress [4]. A¦Â fibrils are toxic by generating oxygen free radicals in the absence of any cellular element [5, 6]. However, synaptic dysfunction and behavioral changes in AD precede the formation of large A¦Â aggregates and fibrils. Indeed, A¦Â dimers and soluble oligomers are considered the major toxic form [7, 8], while fibrils-induced oxidative stress operates late in the course of AD. Thus, the mechanisms through which A¦Â exerts its toxic effect at the early stages of AD remain still to be clarified. Recent evidences suggest that age-relate cofactors
%U http://www.hindawi.com/journals/ijad/2012/734956/