Caspase cleavage of APP contributes to amyloid beta-protein induced synaptic injury.

Background: Increasing evidence suggests that amyloid beta (Aβ) lies at the center of Alzheimer's Disease (AD) pathology and that synapses are the initial site of damage by Aβ. Recent studies have also indicated a role for caspases in AD-related synaptic dysfunction and memory loss, but the mechanism(s) through which the caspases act remains elusive. Previous studies in cell culture indicate that cleavage of a caspase site on the intracellular domain of the amyloid precursor protein (APP) protein contributes to Aβ-induced cell death.

Ethnic variation and structure-function analysis of tauopathy-associated alleles.

EIF2AK3, also known as PERK, plays a pivotal role in cellular proteostasis, orchestrating the Unfolded Protein Response (UPR) and Integrated Stress Response (ISR) pathways. In addition to its central position in intracellular stress regulation, human GWAS identify EIF2AK3 as a risk factor in tauopathies, neurodegenerative diseases caused by aberrant tau protein accumulation. Guided by these genomic indicators, our investigation systematically analyzed human PERK variants, focusing on those with potential tauopathy linkages.

Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation.

Tauopathies are neurodegenerative diseases caused by pathologic misfolded tau protein aggregation in the nervous system. Population studies implicate EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3), better known as PERK (protein kinase R-like endoplasmic reticulum kinase), as a genetic risk factor in several tauopathies. PERK is a key regulator of intracellular proteostatic mechanisms-unfolded protein response and integrated stress response.

Caspase Activation and Caspase-Mediated Cleavage of APP Is Associated with Amyloid β-Protein-Induced Synapse Loss in Alzheimer's Disease.

Amyloid β-protein (Aβ) toxicity is hypothesized to play a seminal role in Alzheimer's disease (AD) pathogenesis. However, it remains unclear how Aβ causes synaptic dysfunction and synapse loss. We hypothesize that one mechanism of Aβ-induced synaptic injury is related to the cleavage of amyloid β precursor protein (APP) at position D664 by caspases that release the putatively cytotoxic C31 peptide.

Regulation of Histone Acetylation by Autophagy in Parkinson Disease.

Parkinson disease (PD) is the most common age-dependent neurodegenerative movement disorder. Accumulated evidence indicates both environmental and genetic factors play important roles in PD pathogenesis, but the potential interaction between environment and genetics in PD etiology remains largely elusive. Here, we report that PD-related neurotoxins induce both expression and acetylation of multiple sites of histones in cultured human cells and mouse midbrain dopaminergic (DA) neurons.

Cellular protection using Flt3 and PI3Kα inhibitors demonstrates multiple mechanisms of oxidative glutamate toxicity.

Glutamate-induced oxidative stress is a major contributor to neurodegenerative diseases. Here, we identify small-molecule inhibitors of this process. We screen a kinase inhibitor library on neuronal cells and identify Flt3 and PI3Kα inhibitors as potent protectors against glutamate toxicity.

In2O3 nanocrystal memory with the barrier engineered tunnel layer.

In2O3 nanocrystal memories with barrier-engineered tunnel layers were fabricated on a p-type Si substrate. The structure and thickness of the barrier-engineered tunnel layers were SiO2/Si3N4/SiO2 (ONO) and 2/2/3 nm, respectively. The equivalent oxide thickness of the ONO tunnel layers was 5.