Control of apoptosis in experimental alzheimer's disease: Therapeutic opportunities for an ancient bile acid

Alzheimer's disease (AD) is recognized as the most severe and common cause of dementia, accounting for 50-60% of all cases. This neurological disorder targets specific brain regions early in its course, including the cholinergic basal forebrain and medial temporal lobe structures, involved in important cognitive functions, such as memory and learning. With disease progression, the pathology spreads to other brain regions, affecting large segments of the brain. Millions of people worldwide develop AD, and in particular people over 65 years old. Since the prevalence of AD increases almost exponentially with age and given the increase in life expectancy, the numbers are expected to reach > 80 million people affected in 2040. More than 100 years after its discovery, AD diagnosis is still difficult and treatment ineffective. Although not completely understood, several abnormal mechanisms are known to be involved in pathogenesis of the disease, such as amyloid β (Aβ)-and tau-induced toxicity and aggregation, synaptic dysfunction, cell cycle deregulation, reactive oxygen species production, inflammation, mitochondrial failure and, ultimately, neuronal cell death. In fact, there is growing evidence to suggest that apoptosis plays a key role in loss of cell numbers. Despite the controversy over the exact role of apoptosis in the pathogenesis of AD, many studies have detected the presence of apoptotic markers in AD brains, underscoring its potential importance. Several efforts have been made to translate advances in the molecular pathogenesis of AD into therapeutic strategies. Although the major goal has been to inhibit Aβ production and aggregation, other therapeutic interventions have focused on modulation of apoptosis. Ursodeoxycholic acid and its taurine conjugate, tauroursodeoxycholic acid (TUDCA) are well-characterized potent inhibitors of apoptosis in different cell types. The potential therapeutic use of these molecules has expanded to a number of experimental models of neurologic disorders, including AD. TUDCA has been shown to regulate precise transcriptional and post-transcriptional events that impact mitochondrial function in neurons. In fact, TUDCA stabilizes the mitochondrial membrane and prevents Bax translocation, inhibiting cytochrome c release and caspase activation, interferes with cell cycle-related proteins, and induces survival pathways. Here, we review the role of apoptosis in AD and discuss the therapeutic potential of TUDCA in treating this disease.