Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop
beta-amyloid deposition resembling plaques in
Alzheimer's disease (AD), results in a decrease of
amyloid burden when compared with non-treated transgenic animals. Immunization with
amyloid-beta 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
meningoencephalitis following immunization with
amyloid-beta peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation with
amyloid deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD4+, 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 Abeta42 and Abeta40, in addition to severe small cerebral blood vessel disease and multiple cortical
hemorrhages. 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 dependent on
beta-amyloid deposition in
neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore,
amyloid reduction was accompanied by increased expression of the PA28a/beta inductor, and of LMP7, LMP2 and MECL1 subunits of the immunoproteasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells. Immunoproteasome subunit expression was accompanied by local presentation of
MHC class I molecules. Release of antigenic
peptides derived from
beta-amyloid processing may enhance T-cell inflammatory responses accounting for the
meningoencephalitis following
amyloid-beta peptide immunization.