Immunosuppressants and Alzheimer’s Disease

Abstract

The two major histopathological abnormalities in the brains of patients with Alzheimer’s disease (AD) are extensive extracellular deposits of amyloid β-peptide (Aβ) and degenerating neurons that contain abnormal hyperphosphorylated filaments composed mainly of the microtubule-associated protein tau (1). Aβ is a 40–42 amino acid peptide that is generated by proteolytic processing of a much larger, membrane-associated amyloid precursor protein (APP). A cleavage of APP in the middle of the Aβ sequence by an enzyme activity called a-secretase results in release of a secreted form of APP called sAPPα, Alternatively, APP can be cleaved at the N and C termini of the Aβ sequence by β-secretase and γ-secretase, respectively. A shift in processing of APP in favor of increased production of neurotoxic forms of Aβ , and decreased production of neuroprotective sAPPa, appears to play a seminal role in the initiation of the neurodegenerative process in AD (2). Indeed, mutations in the APP gene (located on chromosome 21), which are causally linked to a small percentage of cases of early-onset inherited AD, result in increased production of Aβ, particularly the highly neurotoxic long form of Aβ (Aβ1–42). Moreover, mutations in two other proteins called presenilin-1 (PS 1; chromosome 14) and presenilin-2 (PS2; chromosome 1) that cause dominantly inherited early-onset forms of AD result in aberrant APP processing (3,4).