Oxidative stress, perturbed calcium homeostasis, and immune dysfunction in Alzheimer's disease

Abstract

Although Alzheimer's disease (AD) may not involve a transmissible agent, it does involve a pathogenic process similar to that of transmissible prion disorders (both involve a protein that adopts an abnormal pathogenic conformation in which it self-aggregates, forming amyloid deposits in and surrounding neurons) and viral dementias such as human immunodeficiency virus (HIV) encephalitis. The clinical presentation of patients with AD is dominated by cognitive deficits and emotional disturbances that result from dysfunction and degeneration of neurons in the limbic system and cerebral cortex. The pathogenic process in the brain involves deposition of insoluble aggregates of amyloid beta-peptide, oxidative stress and calcium dysregulation in neurons, and activation of inflammatory cytokine cascades involving microglia. However, AD patients also exhibit alterations in immune function. Studies of lymphocytes and lymphoblast cell lines from AD patients and age-matched normal control patients have documented alterations in cytokine and calcium signaling and increased levels of oxidative stress in immune cells from the AD patients. Studies of the pathogenic actions of mutations in presenilins and amyloid precursor protein that cause early-onset familial AD have established central roles for perturbed cellular calcium homeostasis and oxidative stress in the neurodegenerative process. Presenilin and amyloid precursor protein (APP) mutations also increase oxidative stress and perturb calcium signaling in lymphocytes in ways that alter their production of cytokines that are critical for proper immune responses. Immune dysfunction occurs prior to clinical symptoms in mouse models of AD, and brain cytokine responses to immune challenge are altered in presenilin mutant mice, suggesting a causal role for altered immune function in the disease process. Interestingly, immunization of AD mice with amyloid beta-peptide can stimulate the immune system to remove amyloid from the brain and can ameliorate memory deficits, suggesting that it may be possible to prevent AD by bolstering immune function.