New Modes of GPCR Signalling

ABSTRACT
Novel Genes and Pathways that Regulate Alzheimer’s Disease
Pathogenesis
Huaxi Xu
Neurodegenerative Disease Research Program, Sanford-Burnham Medical Research
Institute,10901 N. Torrey Pines Rd.,La Jolla, CA 92037
Alzheimer's disease (AD) is the most common neurodegenerative disorder, afflicting
millions of aged people in the world. Extraneuronal plaques consisting of β-amyloid
(Aβ) peptides, intracellular neurofibrillary tangles (NFTs) composed of
hyperphosphorylated paired helical filaments of the tau protein, and extensive neuronal
loss are major pathological hallmarks of AD. Multiple lines of evidence suggest that
overproduction/aggregation of the neurotoxic Aβ peptide in the brain is a prime culprit
in AD pathogenesis, causing dramatic neuronal death directly responsible for the
cognitive decline in AD patients. Hyperphosphorylated tau has also been found in many
other neurodegenerative diseases (tauopathies). Hence, knowledge of mechanisms
underlying Aβ generation, tau hyperphosphorylation, and neuronal cell death is crucial
for disease intervention; identification of new genes/proteins involved in these
processes is a major goal of AD research. Our group has recently identified two new
players important in AD: 1) RPS23R1, whose gene originated through retroposition of
the ribosomal protein S23 gene, can reduce Aβ level and tau phosphorylation in cell
cultures and alleviate these AD-like pathologies in the APP/PS1/tau triple transgenic
AD mouse model. Detailed mechanistic studies revealed that RPS23R1 can interact
with adenylate cyclases to increase cAMP synthesis, which upregulates PKA activity,
inhibiting GSK-3 activity which is important in modulating Aβ generation and tau
phosphorylation. 2) Appopstosin is an APP-interacting protein that we identified
through yeast-two-hybrid screens. When overexpressed, appoptosin can induce intrinsic
caspase-dependent apoptosis. Importantly, we find that the level of appoptosin is
upregulated in neurons treated with Aβ, glutamate, or ischemia insults as well as in
AD brains. Furthermore, downregulation of appoptosin can protect neurons against
Aβ- and glutamate-induced neurotoxicity.
Together our studies demonstrate that RPS23R1 is beneficial for inhibiting Aβ
generation and tau phosphorylation, whereas appoptosin-mediated apoptosis plays an
important role in neurotoxicity-induced cell death and neurodegenerative diseases.
These studies will provide new therapeutic possibilities for AD treatment.