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. 2006 Apr 5;14(1):11–20. doi: 10.1111/j.1750-3639.2004.tb00493.x

Neuropathology and Pathogenesis of Encephalitis following Amyloid β Immunization in Alzheimer's Disease

Isidre Ferrer 1,2,7,✉, Mercé Boada Rovira 3,4, María Luisa Sánchez Guerra 5, María Jesús Rey 2, Frederic Costa‐Jussá 6
PMCID: PMC8095815  PMID: 14997933

Abstract

Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop β‐amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non treated transgenic animals im‐munization with amyloid β peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of menigoencephalitis following immunization with amyloid‐β peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation‐ with amyliod deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD3+, CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense(collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense Aβ42and Aβ40, in addition to severe small cerebral blood Reduced amyloid burden was accompanied by low amyloid‐associated oxidative stress responses (reduced superoxide dismutase‐1:SOD‐1 expression) and by local inhibition of the stress‐activated protein kinase/c‐Jun N‐terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau in neurofibrillary tangles and β‐amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28α/β inductor, and of LMP7, LMP2 and MECL1 subunits of the immunopro‐teasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells.Immunoproteasome subunit expression was accompanied by local presentation of MHC class molecules. Release of antigenic peptides derived from β‐amyloid processing may enhance T‐cell inflammatory responses accounting for the meningoencephalitis following amyloid‐β peptide immunization

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