Consequences of beta‐amyloid immunotherapy for Alzheimer's disease on neurons in the human cerebral cortex

Boche, Delphine, Amin, Jay, Mouton-Liger, François, Nasser, Mariam, Love, Seth, Gray, Françoise, Pickering, Ruth, Nicoll, James, Holmes, Clive, Hugon, Jacques and Paquet, Claire (2013) Consequences of beta‐amyloid immunotherapy for Alzheimer's disease on neurons in the human cerebral cortex. Alzheimer's & Dementia, 9 (4S, Part 7), P284. (doi:10.1016/j.jalz.2013.05.571).

Abstract

Background: Alzheimer's disease (AD) patients in Aβ immunotherapy trials have demonstrated amyloid plaque removal but with little evidence of slowed cognitive decline. We have explored the consequences of immunotherapy on neuronal density and the morphology of neuronal processes.Methods:11 immunised AD patients (iAD) (Elan Pharmaceuticals, AN1792) were compared to 28 non‐immunised AD patients (cAD) as controls. Immunohistochemistry on sections of cortex from frontal, temporal and parietal lobes was performed for: neuron‐specific nuclear antigen (NeuN), neurofilament (NFP) and pPKR (phosphorylated pro‐apoptotic kinase detected in degenerating neurons). Status spongiosus (neuropil degeneration) was assessed in haematoxylin‐and eosin‐stained sections. We quantified NFP and pPKR labelling as load (%), the percentage area of cortex showing status spongiosus, NeuN‐positive neurons/field, curvature of the neuronal processes and interneuronal distance (m m). Data were corrected for age, gender, duration of dementia and APOE genotype.Results:Our data show in the iAD compared to the cAD cases: a significantly higher degree of spongiosus (53.3 vs 48.6, P = 0.013), fewer NeuN‐positive neurons/field (66.8 vs 73.7, P = 0.036), lower curvature of neuronal processes (1.13 vs 1.23, P < .001), a trends towards a lower pPKR load (0.08 vs 0.16, P = 0.070) and no‐significant change in mean interneuronal distance (713.6 vs 705.2, P = 0.370).Conclusions:After immunisation, there is evidence of enhanced neuronal damage in the form of exacerbated status spongiosus and a lower density of neurons. Remaining neurons seem “healthier” (less curvature of neuronal processes, less pPKR). The data raise the possibility that A β immunisation may accelerate the removal of neurons damaged by AD and are consistent with the report of increased cerebral atrophy detected with MRI.

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Contributors

Author: Delphine Boche

Author: Jay Amin

Author: James Nicoll

Author: Clive Holmes

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