expected to increase to 11 to 16 million by 2050 when the baby boomers age.
The cognitive function of an AD patient deteriorates irreversibly over time and
complete care is required for basic daily activities in the late stages of the
disease. In 2000, health care costs for AD patients in the United States totaled
approximately $31.9 billion, which is expected to reach $49.3 billion by 2010
(above statistics can be found at http://www.alz.org
/). Therefore, AD is a major
and rapidly growing public health concern.
The exact molecular mechanisms leading to the clinical symptoms and
neuropathological changes associated with AD remain unclear. Selective brain
neuronal loss, extracellular amyloid (senile) plaques, and intracellular
neurofibrillary tangles (NFT) of hyperphosphorylated tau protein are
characteristically seen in the brains of AD patients [1, 2]. According to the
widely-accepted “amyloid hypothesis” [3, 4], an unusual accumulation of beta-
amyloid peptides (A!), cleavage products of the amyloid precursor proteins
(APP), are the major cause of AD in its earliest stages. In Familial Alzheimer
Disease (FAD), genetic defects code for abnormal variants of either the APP or
presenilin (PSEN1, PSEN2)— often leading to abnormal formation of A! as
“protofibrils” . A! protofibrils can incite inflammatory response through
cytotoxic cytokines and disrupt intracellular Ca
homeostasis through over-
activation of glutamate receptors, therefore leading cells to oxidative stress and
mitochondrial injury. A! protofibrils deposit in the extracellular space which
may also cause neuronal cell damage by blocking axonal transport. Aberrant A!
accumulation further causes aberrant accumulation of tau, a protein which
normally is essential to the initiation and stabilization of the neuronal
microtubules. As time going by, gradual breakdown of neuronal cytoskeleton
eventually leads to neuron apoptosis in AD patients (For a comprehensive
review, see [1, 2] and references therein). The complexity and broad range of
these cellular and biochemical events make researchers believe that there must
be a sophisticated network of AD signal transduction, gene regulation, and
protein-protein interaction events. Therefore, deciphering AD-related molecular
network “circuitry” can help researchers understand AD disease model details
and propose treatment ideas.
In this work, we will conduct initial AD-protein interaction network
analysis and demonstrate how to gain protein functional knowledge not directly
implied from sequence information. We will organize the main body of the
work by presenting our computational data analysis methods and results. We
will discuss potential interpretations and significance of our results at the end.
Pacific Symposium on Biocomputing 11:367-378(2006)