Immunization therapy for Alzheimer disease?

Alzheimer disease (AD) is characterized pathologically by the accumulation of cortical neuritic plaques and neurofibrillary tangles. Neuritic plaques are composed of a central core of amyloid-β (Aβ) peptide fibrils associated with swollen and tortuous dystrophic neurites, reactive microglia and astrocytes, and glial filaments. Neurofibrillary tangles are composed of abnormally phosphorylated intracellular tau proteins wound into paired helical filaments. Evidence suggests that deposition of Aβ is a primary step in a cascade of events that ultimately leads to the loss of memory and other cognitive abilities that characterizes AD.1–3⇓⇓ First, all three genetic mutations that cause early onset, autosomal dominant, familial AD in the amyloid precursor protein, presenilin 1, and presenilin 2 (chromosomes 21, 14, and 1) result in the increased production of Aβ. Second, the genetic risk factor for AD, apolipoprotein E (apoE) genotype (chromosome 19, ε4 increases risk, ε2 decreases risk), appears to result from apoE acting as an Aβ chaperone, differentially influencing Aβ clearance and fibrillogenesis. Third, in trisomy 21, Aβ appears to be deposited prior to the accumulation of neurofibrillary tangles. Finally, mutations in the tau gene cause a degenerative dementia with tangle formation but without deposition of Aβ. These data suggest that therapeutic interventions that prevent the deposition of Aβ or promote its clearance could be a viable strategy for disease treatment and/or prevention.

Much has been learned about the processing of the Aβ peptide in the 20 years since Glenner and Wong first purified the protein. The Aβ protein that accumulates in AD is a 38 to 43 amino acid peptide derived from a much larger transmembrane protein, the amyloid precursor protein. The Aβ peptide is produced by cleavage of the precursor protein by the enzymes β-secretase and γ-secretase. By contrast, cleavage of the precursor protein with α-secretase prevents the formation of …