β-Amyloid Neurotoxicity Is Exacerbated during Glycolysis Inhibition and Mitochondrial Impairment in the Rat Hippocampus in Vivo and in Isolated Nerve Terminals: Implications for Alzheimer's Disease

Adenosine A2AReceptor Blockade Prevents Synaptotoxicity and Memory Dysfunction Caused by β-Amyloid Peptides via p38 Mitogen-Activated Protein Kinase Pathway

“…Accordingly, in cultured neurons (in which peripheral, vascular, glial, or immune influences are absent), we also found that exposure to A␤ caused first a synaptotoxicity (Roselli et al, 2005;Calabrese et al, 2007;Shankar et al, 2007;Evans et al, 2008), which is only later followed by overt neuronal damage. Further strengthening that A␤ causes direct effects on nerve terminals, we showed that A␤ indeed directly impairs synaptosomal function, as observed by others (Mattson et al, 1998;Arias et al, 2002). Together, these observations indicate that A␤, which can bind to synaptic proteins (Lacor et al, 2007) and accumulates synaptically in AD patients (Takahashi et al, 2002;Gylys et al, 2004;Fein et al, 2008), causes a primordial synaptotoxicity that precedes overt neuronal damage, as occurs in different transgenic animal models of AD (Hsia et al, 1999;Mucke et al, 2000;Oddo et al, 2003;Wu et al, 2004;Jacobsen et al, 2006) and in frontal cortical and hippocampal regions early in AD (Scheff et al, 2006(Scheff et al, , 2007.…”

Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment

“…The pathologies may simply induce catalytic changes in the enzymes, an idea supported by energy metabolism changes in transgenic mouse models of AD (Dodart et al, 1999;Reiman et al, 2000;Strazielle et al, 2003;Reddy et al, 2004;Caspersen et al, 2005;Valla et al, 2006). Conversely, energy inhibition can alter APP processing in cultured cells (Gabuzda et al, 1994), in mouse models of amyloid overexpression, increasing β-secretase activity and amyloidogenicity (Velliquette et al, 2005), and in rats, exacerbating Aβ peptide toxicity, particularly in synapses (Arias et al, 2002). Also, mitochondrial involvement in AD etiology is supported by studies using a cybrid cell model, which utilizes mtDNA-depleted cultured cells re-populated with AD patient or control mitochondria.…”

3-Nitropropionic acid toxicity in hippocampus: Protection throughN-methyl-D-aspartate receptor antagonism

“…The toxin acts by inhibiting succinate dehydrogenase and disrupting cellular metabolism (Ludolph et al, 1992). 3-NPinduced toxicity has been used as an experimental model for certain age-related neurodegenerative diseases (Beal et al, 1993;Miller and Zaborszky, 1997;Bizat et al, 2003), and has been established in vivo to exacerbate b-amyloid neurotoxicity (Arias et al, 2002). In our study we made use of organotypic slice cultures prepared from the hippocampus, a brain region targeted by a variety of neurological disorders, including stroke and AD.…”