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

Abstract

Aβ immunisation 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 immunisation, we have assessed the impact of previous Aβ immunisation on the expression of a range of apoptotic proteins in post-mortem human brain tissue. Cortex from 13 AD patients immunised with AN1792 (iAD) and from 27 non-immunised AD (cAD) cases was immunolabelled for pro-apoptotic proteins implicated in AD pathophysiology: phosphorylated c-Jun N-terminal kinase (pJNK), activated caspase3 (a-casp3), phosphorylated GSK3β on tyrosine 216 (GSK3βtyr216), p53 and Cdk5/p35. Expression of these proteins was analysed in relation to immunisation status and other clinical data. The antigen load of all of these pro-apoptotic proteins was significantly lower in iAD than cAD (p < 0.0001). In cAD, significant correlations (p < 0.001) were observed between: Cdk5/p35 and GSK3βtyr216; a-casp3 and Aβ42; p53 and age at death. In iAD, significant correlations were found between GSK3βtyr216 and a-casp3; both spongiosis and neuritic curvature ratio and Aβ42; and Cdk5/p35 and Aβ-antibody level. Although neuronal loss was increased by immunisation with AN1792, our present findings suggest downregulation of apoptosis in residual neurons and other cells.

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Identifiers

ORCID for James Nicoll: orcid.org/0000-0002-9444-7246

ORCID for Clive Holmes: orcid.org/0000-0003-1999-6912

ORCID for Delphine Boche: orcid.org/0000-0002-5884-130X

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