Alzheimer disease (AD) is the most common form of age-related dementia. The etiology of AD is considered to be multifactorial as only a negligible percentage of cases have a familial or genetic origin. Glycogen synthase kinase-3 (GSK-3) is regarded as a critical molecular link between the two histopathological hallmarks of the disease, namely senile plaques and neurofibrillary tangles. In this review, we summarize current data regarding the involvement of this kinase in several aspects of AD development and progression, as well as key observations highlighting GSK-3 as one of the most relevant targets for AD treatment.

Disease and hippocampal dysfunction: Impaired function of the brain’s hippocampus can underpin psychiatric symptoms and cognitive impairment. Looking at postmortem brain samples from patients affected by any of several neurodegenerative disorders, Terreros-Roncal et al . investigated whether adult neurogenesis was disrupted (see the Perspective by Gage). Indeed, functions of the neurogenic niche shifted and the cells produced were abnormal in shape and differentiation. The neuronal plasticity characteristic of the hippocampus may make it especially susceptible to the ravages of neurodegenerative disease. —PJH

The rodent hippocampus generates new neurons throughout life. This process, named adult hippocampal neurogenesis (AHN), is a striking form of neural plasticity that occurs in the brains of numerous mammalian species. Direct evidence of adult neurogenesis in humans has remained elusive, although the occurrence of this phenomenon in the human dentate gyrus has been demonstrated in seminal studies and recent research that have applied distinct approaches to birthdate newly generated neurons and to validate markers of adult-born neurons. Our data point to the persistence of AHN until the 10th decade of human life, as well as to marked impairments in this process in patients with Alzheimer's disease. Moreover, our work demonstrates that the methods used to process and analyze postmortem human brain samples can limit the detection of various markers of AHN to the point of making them undetectable. In this Dual Perspectives article, we highlight the critical methodological aspects that should be strictly controlled in human studies and the robust evidence that supports the occurrence of AHN in humans. We also put forward reasons that may account for current discrepancies on this topic. Finally, the unresolved questions and future challenges awaiting the field are highlighted.

The microtubule-associated protein (MAP) tau plays a critical role in the pathogenesis of tauopathies. Excess tau can be released into the extracellular medium in a physiological or pathological manner to be internalized by surrounding neurons—a process that contributes to the spread of this protein throughout the brain. Such spreading may correlate with the progression of the abovementioned diseases. In addition to neurons, tau can be internalized into other cells. Here we demonstrate that microglia take up tau in vitro and in vivo. In this regard, microglia from primary cultures internalized soluble (human recombinant tau42) and insoluble (homogenates derived from human AD brain) tau in vitro. Furthermore, using stereotaxic injection of tau in mice in vivo, we show that murine microglia internalize human tau. In addition, we demonstrate, for the first time, that microglia colocalize with various forms of tau in postmortem brain tissue of patients with Alzheimer’s disease and non-demented control subjects. Our data reveal a potential role of microglia in the internalization of tau that might be relevant for the design of strategies to enhance the clearance of extracellular tau in neurodegenerative diseases characterized by the accumulation of this protein.