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Abstract
The distribution of abnormally phosphorylated tau proteins was investigated in a number
of cortical areas and in the basal nucleus of Meynert of 12 patients with Alzheimer's
disease. Quantification was performed with a sensitive sandwich enzyme-linked immunosorbent
assay employing the monoclonal antibody B5-2, which immunoreacts with neurofibrillary
tangles, dystrophic neurites surrounding amyloid cores of plaques and neuropil threads.
On western blots, the monoclonal antibody B5-2 specifically labels the abnormally
phosphorylated paired helical filament-tau species in a phosphorylation-dependent
manner but is not cross-reactive to normal tau proteins. The preferential involvement
of cytoarchitecturally defined cortical areas showed marked individual differences
in Alzheimer's disease, and no unique distribution pattern of abnormally phosphorylated
tau proteins could be established. While regional heterogeneities along the rostrocaudal
extension of the brain declined with the progression of the disease, lateral differences
which were largely non-directional appeared to be more stable over time. The mean
content of abnormally phosphorylated tau proteins of individual cases was significantly
related to the severity of the disease. On a regional scale, this correlation was
highest for the basal nucleus. The formation of abnormally phosphorylated tau was
associated with a loss of normal soluble tau proteins. Those cortical areas which
in normal brain showed the highest amount of normal soluble tau proteins appeared
to be particularly prone to deposition of abnormally phosphorylated tau proteins.
The present results indicate that the formation of abnormally phosphorylated tau proteins
can be initiated in the neuropil at more than one brain area. The spreading of the
pathology appears to involve both intracortical and subcortical pathways but largely
spares interhemispheric pathways. It is hypothesized that regional differences in
the compartmentation and metabolism of tau proteins might reflect the molecular basis
for the regionally different vulnerability in Alzheimer's disease.