DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3.

Apoptotic pathways and DNA synthesis are activated in neurons in the brains of individuals with Alzheimer disease (AD). However, the signaling mechanisms that mediate these events have not been defined. We show that expression of familial AD (FAD) mutants of the amyloid precursor protein (APP) in primary neurons in culture causes apoptosis and DNA synthesis.

A monoclonal antibody to amyloid precursor protein induces neuronal apoptosis.

Although there is considerable evidence suggesting that altered metabolism of beta-amyloid precursor protein (APP) and accumulation of its beta-amyloid fragment are key features of Alzheimer's disease (AD), the normal physiological function of APP remains elusive. We investigated the potential role of APP in neurons using the monoclonal antibody 22C11, which binds to the extracellular domain of the human, rat, or mouse APP. Exposure of cortical neurons to 22C11 induced morphological changes including neurite degeneration, nuclear condensation, and internucleosomal DNA cleavage that were consistent with neurons dying by apoptosis.

Expression of metabotropic glutamate receptor 5 is increased in astrocytes after kainate-induced epileptic seizures.

In the CNS there is a differential distribution of the metabotropic glutamate receptor 5 (mGluR5) in neurons and glia. Hippocampal nerve cells contain large amounts of the receptor transcript and protein that are expressed at very low levels in astrocytes. This is unexpected, as mGluR-induced phosphoinositide hydrolysis is substantial in cultured astrocytes and is mediated only by mGluR5 in these cells.

Neuronal apoptosis induced by beta-amyloid is mediated by caspase-8.

The Alzheimer disease-associated beta-amyloid peptide has been shown to induce apoptotic neuronal death. In the present study, we test the hypothesis that the apoptotic pathway activated by beta-amyloid is similar to the pathway activated by the Fas/TNFR family of death receptors, which requires caspase-8 activity and adaptor proteins such as FADD. We demonstrate that the selective caspase-8 inhibitor IETD-fmk blocks neuronal death induced by beta-amyloid.

Bcl-2 facilitates recovery from DNA damage after oxidative stress.

Oxidative stress is a major factor affecting the brain during aging and neurodegenerative diseases such as Alzheimer's disease (AD). Understanding the mechanisms by which neurons can be protected from oxidative stress, therefore, is critical for the prevention and treatment of such degeneration. Previous studies have shown that bcl-2 expression is increased in neurons with DNA damage in AD and bcl-2 has an antioxidant effect.