Seite - (000183) - in Biomedical Chemistry: Current Trends and Developments

beta (Aβ) peptides that form senile plaques, neurofibrillary tangles of hyperphosphorylated tau and neuronal loss (Parameshwaran, 2008). Several studies have demonstrated that excitatory synaptic transmission and plasticity are impaired in the hippocampus of AD, and particularly the glutamatergic system is altered leading to synaptic dysfunction and neurodegeneration (Parameshwaran, 2008). Several studies demonstrated that levels of VGLUTs are decreased, particularly VGLUT1, in AD patient’s cortices, and that Aβ peptides accumulate preferentially in glutamatergic neurons, expressing VGLUT1/2 (Sokolow, 2012). Also, EAAT levels are reduced, indicating that glutamate reuptake from the synaptic cleft is compromised (Scott, 2011). Furthermore, glutamate synthase levels are reduced, increasing glutamate levels in astrocytes, which can be released to the synaptic cleft (Robinson, 2001). These effects may increase glutamate levels at the synapse, triggering excitotoxic mechanisms that will contribute to cell death in AD (Dong, 2009). It has been hypothesized that changes in AMPA receptors (AMPARs) number and function play an important role in AD pathogenesis. Various studies reported a downregulation of AMPARs by Aβ peptides at initial stages of the disease, probably related to a synaptic failure underlying initial cognitive impairment, prior to neuronal loss (Selkoe, 2002). This reduction of AMPARs levels contributes to loss of synaptic function at initial stages of the disease, and is related to caspase cleavage or endocytosis of the receptors triggered by Aβ peptides (Chan, 1999; Chang, 2006). Moreover, Aβ affects proteins related to AMPARs insertion and stabilization at the plasma membrane, such as post-synaptic density protein 95 (PSD-95) in a NMDA receptors (NMDARs) dependent mechanism (Roselli, 2005). Excitotoxic neuronal death triggered by excessive glutamate at the synapse and sustained Ca2+ influx through NMDARs is believed to be one of the major causes of neurodegeneration in AD (Harkany, 2000). Abnormal NMDARs upregulation contribute to elevated production of Aβ, resulting in increased glutamate levels and activation of NMDARs as disease progresses, indicating that NMDARs play a key role in Aβ induced neurotoxicity (Miguel-Hidalgo, 2002). It is also believed that a functional downregulation of NMDARs at initial stages of the disease is related to a compromised glutamatergic function. Aβ peptides reduce surface NMDARs levels at the synapse through endocytosis, which depresses the