Amyloid-β (Aβ) toxicity in Alzheimer's disease (AD) is considered to be mediated by phosphorylated tau protein. In contrast, we found that, at least in early disease, site-specific phosphorylation of tau inhibited Aβ toxicity. This specific tau phosphorylation was mediated by the neuronal p38 mitogen-activated protein kinase p38γ and interfered with postsynaptic excitotoxic signaling complexes engaged by Aβ. Accordingly, depletion of p38γ exacerbated neuronal circuit aberrations, cognitive deficits, and premature lethality in a mouse model of AD, whereas increasing the activity of p38γ abolished these deficits. Furthermore, mimicking site-specific tau phosphorylation alleviated Aβ-induced neuronal death and offered protection from excitotoxicity. Our work provides insights into postsynaptic processes in AD pathogenesis and challenges a purely pathogenic role of tau phosphorylation in neuronal toxicity.

Aims Neurogenesis in the postnatal human brain occurs in two neurogenic niches; the subventricular zone (SVZ) in the wall of the lateral ventricles and the subgranular zone of the hippocampus (SGZ). The extent to which this physiological process continues into adulthood is an area of ongoing research. This study aimed to characterise markers of cell proliferation and assess the efficacy of antibodies used to identify neurogenesis in both neurogenic niches of the human brain. Methods Cell proliferation and neurogenesis were simultaneously examined in the SVZ and SGZ of 23 individuals aged 0.2–59 years using immunohistochemistry and immunofluorescence in combination with unbiased stereology. Results There was a marked decline in proliferating cells in both neurogenic niches in early infancy with levels reaching those seen in the adjacent parenchyma by four and one year of age, in the SVZ and SGZ, respectively. Furthermore, the phenotype of these proliferating cells in both niches changed with age. In infants, proliferating cells co-expressed neural progenitor (epidermal growth factor receptor), immature neuronal (doublecortin and beta III tubulin) and oligodendrocytic (Olig2) markers. However, after three years of age, microglia were the only proliferating cells found in either niche or in the adjacent parenchyma. Conclusions This study demonstrates a marked decline in neurogenesis in both neurogenic niches in early childhood, and that the sparse proliferating cells in the adult brain are largely microglia.

Immunization is increasingly recognized as a suitable therapeutic avenue for the treatment of neurological diseases such as Alzheimer's disease and other tauopathies. Tau is a key molecular player in these conditions and therefore represents an attractive target for passive immunization approaches. We performed such an approach in two independent tau transgenic mouse models of tauopathy, K369I tau transgenic K3 and P301L tau transgenic pR5 mice. The antibodies we used were either specific for full-length tau or tau phosphorylated at serine 404 (pS404), a residue that forms part of the paired helical filament (PHF)-1 phosphoepitope that characterizes tau neurofibrillary tangles in tauopathies. Although both pS404 antibodies had a similar affinity, they differed in isotype, and only passive immunization with the IgG2a/j pS404-specific antibody resulted in a lower tangle burden and reduced phosphorylation of tau at the PHF1 epitope in K3 mice. In pR5 mice, the same antibody led to a reduced phosphorylation of the pS422 and PHF1 epitopes of tau. In addition, histological sections of the hippocampal dentate gyrus of the immunized pR5 mice displayed reduced pS422 staining intensities. These results show that passive immunization targeting tau can modulate aspects of tau pathology in tau transgenic mouse models, in an antibody isotype-specific manner.