Alzheimer's Disease

Alzheimer's disease (AD) is a global public health threat, and will likely surpass cancer as the leading cause of death in the 21st century. The number of individuals afflicted with this debilitating disease continues to rise and is estimated to exceed 13.8 million by 2050. Despite this urgent need, current treatment options are limited to symptomatic relief that is effective in a small number of patients for only a few months.  In addition, the  current success rate for AD clinical trials is 0.4%. An elegant solution to the AD drug discovery problem is the development of innovative therapies that normalize the early dysregulation of Ca2+ signaling that drives  cognitive impairment in all forms of the disease. Ca2+ dyshomeostasis is increasingly implicated in initiating or accelerating a wide range of disease features, including amyloid and tau histopathology, synaptic plasticity inflammatory responses, excitotoxicity and ultimately cognitive deficits. This early Ca2+ dysregulation originates predominantly from ER stores and is mediated through the inositol triphosphate and ryanodine receptor  channels, but can also be triggered by plasma membrane Ca2+ channels such as NMDAR. The increased [Ca2+]i  can then directly activate numerous downstream enzymes, kinases and phosphatases  as well as the Ca2+ sensor proteins responsible for transducing changes in  [Ca2+]i  into biological responses.   

All 21 members of the S100 family of Ca2+ sensor proteins encoded in the human genome are expressed in the human brain (http://human.brain-map.org). Polymorphisms in the S100B gene are associated with increased risk of AD/dementia, and seven family members (S100A1, S100A6, S100A7, S100A8, S100A9, S100A12 and S100B) exhibit increased expression/activity in AD. Studies in animal models have shown that  S100A1, S100A7, S100A9 and S100B actively contribute to disease pathobiology. Although S100 proteins have very similar structures, individual family members are not functionally interchangeably and have distinct cellular mechanisms of action.  S100A7 selectively activates "non-amyloidogenic" alpha-secretase activity and is the only family member that is neuroprotective.  S100A9 promotes cognitive decline, amyloidosis and neuroinflammation.  S100A1 and S100B also promote amyloidosis and neuroinflammation as well as Ca2+ dysregulation, but utilize distinct mechanisms of action.  S100A1 is expressed primarily in neurons and regulates ryanodine receptor channel activity. S100B is expressed primarily in astrocytes, and when released exerts trophic effects at low concentrations and toxic effects at higher concentrations.  Upregulation of S100B expression by the toxic Ab peptide, generates a feedforward loop and detrimental “cytokine cycle” that drives disease progression.  Our ongoing studies on S100A1 and S100B signaling in AD will provide new targets for drug discovery and facilitate the development of new therapies to treat this costly and debilitating disease.