Caspase‐cleaved Amyloid Precursor Protein in Alzheimer's Disease

Abstract

Caspase-3 mediated cleavage of the amyloid precursor protein (APP) has been proposed as a putative mechanism underlying amyloidosis and neuronal cell death in Alzheimer's disease (AD). We utilized an antibody that selectively recognizes the neo epitope generated by caspase-3 mediated cleavage of APP (␣⌬C csp -APP) to determine if this proteolytic event occurs in senile plaques in the inferior frontal gyrus and superior temporal gyrus of autopsied AD and age-matched control brains. Consistent with a role for caspase-3 activation in AD pathology, ␣⌬C csp -APP immunoreactivity colocalized with a subset of TUNEL-positive pyramidal neurons in AD brains. ␣⌬C csp -APP immunoreactivity was found in neurons and glial cells, as well as in smalland medium-size particulate elements, resembling dystrophic terminals and condensed nuclei, respectively, in AD and age-matched control brains. There were a larger number of ␣⌬C csp -APP immunoreactive elements in the inferior frontal gyrus and superior temporal gyrus of subjects with AD pathology than age-matched controls. ␣⌬C csp -APP immunoreactivity in small and medium size particulate elements were the main component colocalized with 30% of senile plaques in the inferior frontal gyrus and superior temporal gyrus of AD brains. In some control brains, ␣⌬C csp -APP immunoreactivity appeared to be associated with a clinical history of metabolic encephalopathy. Our results suggest that apoptosis contributes to cell death resulting from amyloidosis and plaque deposition in AD.

Caspase-3 Is Enriched in Postsynaptic Densities and Increased in Alzheimer's Disease

“…Previous immunohistochemical studies have shown immunoreactivity of active caspase-3 and caspase-3-cleaved substrates in neurons, senile plaques, and neurofibrillary tangles in AD, 17,18,38,39,[57][58][59][60] although not all investigators have reported these findings. 61 Of note is that none of these previous studies have focused on caspase-3 in synaptic terminal fields or neuropil.…”

Caspase-8 Mediates Amyloid-β-induced Apoptosis in Differentiated PC12 Cells

“…Caspase activation was involved in apoptosis (Cohen, 1997;Ayala-Groeso et al 2002;Amano et al 2005;Denecker et al 2008;Pop and Salvesen 2009;Hyman andYuan 2012, 2012). The two classical apoptotic pathways are the intrinsic, or mitochondrial pathway, and the extrinsic pathway.…”

“…Early studies found that the cysteine-aspartic protease (caspase) family is involved in apoptosis (Ayala-Groeso et al 2002;Hyman and Yuan 2012). There are 15 different caspases known in mammals and 11 in humans (Pop and Salvesen 2009).…”

Quercetin 3-Glucoside Protects Neuroblastoma (SH-SY5Y) Cells in Vitro against Oxidative Damage by Inducing Sterol Regulatory Element-binding Protein-2-mediated Cholesterol Biosynthesis

“…Pretreatment with Q3G prior to the oxidative insult significantly decreased the number of TUNEL-positive cells. To further evaluate the mechanism of cell death induced by H 2 O 2 , Western blot analysis was carried out using an antibody that detects caspase-3-cleaved spectrin (36). In SH-SY5Y cells treated with H 2 O 2 , higher levels of caspase-3-cleaved spectrin were detected compared with untreated cells (data not shown).…”