A monoclonal antibody to the microtubuleassociated protein X (tau) labeled some neurofibrillary tangles and plaque neurites, the two major locations of paired-helical

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A strong immunoreactivity for ferritin was observed in the neuritic (senile) plaques in Alzheimer's disease hippocampus. The ferritin accumulation was almost exclusively associated with the microglia, which appeared to have proliferated greatly. These cells were also positive for HLA-DR, a putative marker for reactive microglia. In contrast, in the diffuse plaques, which were without neuritic pathology, the ferritin-stained microglia appeared to be normal. Microglia were seen frequently in contact with neurons undergoing neurofibrillary changes but only the tangles in the extracellular space were ferritin positive. No ferritin was detected, by Western blots, in paired helical filaments isolated from Alzheimer's disease brain, suggesting that ferritin was most likely weakly associated with and was not a constituent of these fibrils. No correlation between increased ferritin/microglia activity and blood-brain barrier leakage was detected. Ferritin, an iron-storage protein, might have a role in the formation of amyloid through the action of free radicals generated during the release of iron from the ferritin molecule. Alternatively, the ferritin/microglia system might be secondarily involved in the removal and processing of the amyloid.

Amino acid sequencing of a CNBr digest of the r protein isolated from bovine brain revealed an amino acid sequence of 17 residues,

BackgroundAccumulation of hyperphosphorylated tau protein is a histopathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Currently, there is no effective treatment available for these progressive neurodegenerative diseases. In recent years, tau immunotherapy has shown great potential in animal models. We report the effect of immunization with tau antibodies 43D against tau 6–18 and 77E9 against tau 184–195 on tau and amyloid-β (Aβ) pathologies and cognition in triple-transgenic (3×Tg)-AD mice at mild to moderate stages of the disease.MethodsWe immunized 12-month-old female 3×Tg-AD mice with two to six or seven intravenous weekly doses of 15 μg of mouse monoclonal antibody 43D, 77E9, a combination of one-half dose each of 43D and 77E9, or as control of mouse immunoglobulin G (IgG). Age-matched wild-type mice treated with mouse IgG or a mixture of 43D and 77E9 were also used as controls. The effect of immunization with tau antibodies on tau and Aβ pathologies was assessed by Western blot and immunofluorescence analysis, and the effect on cognition was analyzed by using Morris water maze, one-trial novel object recognition, and novel object location tasks.ResultsWe found that two doses of 43D and 77E9 reduced total tau but had no significant impact on hyperphosphorylation of tau. However, six doses of 43D reduced levels of both total tau and tau hyperphosphorylated at Ser262/356 and Ser396/404 sites in the hippocampus. Importantly, both 43D and 77E9 antibodies rescued spatial memory and short-term memory impairments in 3×Tg-AD mice. The beneficial effect of 43D and 77E9 antibodies on cognitive performance was sustained up to 3 months after the last dose. Six doses of immunization with 43D also decreased amyloid precursor protein (APP) level in CA1 and amyloid plaques in subiculum, and showed a trend toward reducing Aβ40 and Aβ42 in the forebrain. Immunization with 43D increased levels of complement components C1 and C9 and resulted in activation of microglia, especially surrounding Aβ plaques.ConclusionsThese findings suggest the potential of passive immunization targeting proximal N-terminal domain tau 6–18 as a disease-modifying approach to AD and related tauopathies.

IntroductionNeurofibrillary pathology of abnormally hyperphosphorylated tau (P‐tau) is a hallmark of Alzheimer's disease (AD) and other tauopathies. Tau pathology can be experimentally induced and propagated. However, what induces the prion‐like transmission character to tau and produces morphologically distinct tau lesions remains elusive.MethodsWe investigated the role of hyperphosphorylation in the spread of tau pathology in hTau transgenic mice.ResultsWe found that intrahippocampal injection with AD P‐tau, but not nonphosphorylated tau, produced numerous P‐tau tangles and neuropil threads locally and in neocortex lateral to injection and upstream to the hippocampus. Dephosphorylation of AD P‐tau with protein phosphatase‐2A dramatically reduced and switched tau pathology from neurofibrillary tangles to argyrophilic grain‐like morphology.ConclusionsOur findings show that abnormal hyperphosphorylation of tau determines the spread and morphology of tau lesions and that the propagation of tau pathology takes place both locally and in axonally connected areas and highlight tau hyperphosphorylation as a potential drug target.