Downregulated apoptosis and autophagy after anti-Aβ immunotherapy in Alzheimer's disease

Aβ immunization of Alzheimer's disease (AD) patients in the AN1792 (Elan Pharmaceuticals) trial caused Aβ removal and a decreased density of neurons in the cerebral cortex. As preservation of neurons may be a critical determinant of outcome after Aβ immunization, we have assessed the impact of previous Aβ immunization on the expression of a range of apoptotic proteins in post-mortem human brain tissue. Cortex from 13 AD patients immunized with AN1792 (iAD) and from 27 nonimmunized AD (cAD) cases was immunolabeled for proapoptotic proteins implicated in AD pathophysiology: phosphorylated c-Jun N-terminal kinase (pJNK), activated caspase3 (a-casp3), phosphorylated GSK3β on tyrosine 216 (GSK3β_tyr216 ), p53 and Cdk5/p35. Expression of these proteins was analyzed in relation to immunization status and other clinical data. The antigen load of all of these proapoptotic proteins was significantly lower in iAD than cAD (P < 0.0001). In cAD, significant correlations (P < 0.001) were observed between: Cdk5/p35 and GSK3β_tyr216 ; a-casp3 and Aβ₄₂ ; p53 and age at death. In iAD, significant correlations were found between GSK3β_tyr216 and a-casp3; both spongiosis and neuritic curvature ratio and Aβ₄₂ ; and Cdk5/p35 and Aβ-antibody level. Although neuronal loss was increased by immunization with AN1792, our present findings suggest downregulation of apoptosis in residual neurons and other cells.