Karin Boekhoorn

Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus.

Adult proliferation and hippocampal neurogenesis are stimulated by injury. In agreement, aberrant cell-cycle-related protein expression has been reported in senile Alzheimers disease (AD), where the hippocampus is particularly affected. Recently, increased expression of doublecortin (DCX), a neurogenesis marker, was reported in senile AD. Here, we addressed whether proliferative and neurogenic responses also occur in younger, i.e., presenile AD cases, using immunohistochemistry for Ki-67, GFAP and DCX. Increased numbers of Ki-67+ cells with a healthy, non-mature appearance were found in CA1-3. These were mainly due to glial and vasculature-associated changes, while DCX immunostaining appeared sensitive to postmortem breakdown. We found no indications for altered dentate gyrus neurogenesis. Our data obtained using validated methodology in a well-characterized, presenile cohort thus differ from previous data obtained in senile AD. They reflect clear differences in proliferative responsivity, particularly in the glia and vascular components, and suggest different underlying mechanisms in these groups.

Improved Long-Term Potentiation and Memory in Young Tau-P301L Transgenic Mice before Onset of Hyperphosphorylation and Tauopathy

The microtubule binding protein tau is implicated in neurodegenerative tauopathies, including frontotemporal dementia (FTD) with Parkinsonism caused by diverse mutations in the tau gene. Hyperphosphorylation of tau is considered crucial in the age-related formation of neurofibrillary tangles (NFTs) correlating well with neurotoxicity and cognitive defects. Transgenic mice expressing FTD mutant tau-P301L recapitulate the human pathology with progressive neuronal impairment and accumulation of NFT. Here, we studied tau-P301L mice for parameters of learning and memory at a young age, before hyperphosphorylation and tauopathy were apparent. Unexpectedly, in young tau-P301L mice, increased long-term potentiation in the dentate gyrus was observed in parallel with improved cognitive performance in object recognition tests. Neither tau phosphorylation, neurogenesis, nor other morphological parameters that were analyzed could account for these cognitive changes. The data demonstrate that learning and memory processes in the hippocampus of young tau-P301L mice are not impaired and actually improved in the absence of marked phosphorylation of human tau. We conclude that protein tau plays an important beneficial role in normal neuronal processes of hippocampal memory, and conversely, that not tau mutations per se, but the ensuing hyperphosphorylation must be critical for cognitive decline in tauopathies.

Changes in adult neurogenesis in neurodegenerative diseases: cause or consequence?

This review addresses the role of adult hippocampal neurogenesis and stem cells in some of the most common neurodegenerative disorders and their related animal models. We discuss recent literature in relation to Alzheimer’s disease and dementia, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, alcoholism, ischemia, epilepsy and major depression.

Doublecortin-like, a microtubule-associated protein expressed in radial glia, is crucial for neuronal precursor division and radial process stability

During corticogenesis, progenitors divide within the ventricular zone where they rely on radial process extensions, formed by radial glial cell (RG) scaffolds, along which they migrate to the proper layers of the cerebral cortex. Although the microtubule‐associated proteins doublecortin (DCX) and doublecortin‐like kinase (DCLK) are critically involved in dynamic rearrangement of the cytoskeletal machinery that allow migration, little is known about their role in early corticogenesis. Here we have functionally characterized a mouse splice‐variant of DCLK, doublecortin‐like (DCL), exhibiting 73% amino acid sequence identity with DCX over its entire length. Unlike DCX, DCL is expressed from embryonic day 8 onwards throughout the early neuroepithelium. It is localized in mitotic cells, RGs and radial processes. DCL knockdown using siRNA in vitro induces spindle collapse in dividing neuroblastoma cells, whereas overexpression results in elongated and asymmetrical mitotic spindles. In vivo knockdown of the DCLK gene by in utero electroporation significantly reduced cell numbers in the inner proliferative zones and dramatically disrupted most radial processes. Our data emphasize the unique role of the DCLK gene in mitotic spindle integrity during early neurogenesis. In addition, they indicate crucial involvement of DCLK in RG proliferation and their radial process stability, a finding that has thus far not been attributed to DCX or DCLK.

Changes in neurogenesis in dementia and Alzheimer mouse models: are they functionally relevant?

Alzheimer’s disease and related dementias are devastating disorders that lead to the progressive decline of cognitive functions. Characteristic features are severe brain atrophy, paralleled by accumulation of beta amyloid and neurofibrillary tangles. With the discovery of neurogenesis in the adult brain, the hopes have risen that these neurodegenerative conditions could be overcome, or at least ameliorated, by the generation of new neurons. The location of the adult neurogenic zones in the hippocampus and the lateral ventricle wall, close to corpus callosum and neocortex, indicates strategic positions for potential repair processes. However, we also need to consider that the generation of new neurons is possibly involved in cognitive functions and could, therefore, be influenced by disease pathology. Moreover, aberrant neurogenic mechanisms could even be a part of the pathological events of neurodegenerative diseases. It is the scope of this review to summarize and analyze the recent data from neurogenesis research with respect to Alzheimer’s disease and its animal models.

Tau-4R suppresses proliferation and promotes neuronal differentiation in the hippocampus of tau knockin/knockout mice

Differential isoform expression and phosphorylation of protein tau are believed to regulate the assembly and stabilization of microtubuli in fetal and adult neurons. To define the functions of tau in the developing and adult brain, we generated transgenic mice expressing the human tau‐4R/2N (htau‐4R) isoform on a murine tau null background, by a knockout/ knockin approach (tau‐KOKI). The main findings in these mice were the significant increases in hippocam‐pal volume and neuronal number, which were sustained throughout adult life and paralleled by improved cognitive functioning. The increase in hippocampal size was found to be due to increased neurogenesis and neuronal survival. Proliferation and neuronal differentiation were further analyzed in primary hippocampal cultures from tau‐KOKI mice, before and after htau‐4R expression onset. In absence of tau, proliferation increased and both neurite and axonal outgrowth were reduced. Htau‐4R expression suppressed proliferation, promoted neuronal differentiation, and restored neu‐rite and axonal outgrowth. We suggest that the tau‐4R isoform essentially contributes to hippocampal development by controlling proliferation and differentiation of neuronal precursors.–Sennvik K., Boekhoorn, K., Lasrado, R., Terwel, D., Verhaeghe, S., Korr, H., Schmitz, C., Tomiyama, T., Mori, H., Krugers, H., Joels, M., Ramakers, G. J. A., Lucassen, P. J., Van Leuven F. Tau‐4R suppresses proliferation and promotes neuronal differentiation in the hippocampus of tau knockin/knockout mice. FASEB J. 21, 2149–2161 (2007)

The microtubule destabilizing protein stathmin controls the transition from dividing neuronal precursors to postmitotic neurons during adult hippocampal neurogenesis

The hippocampus is one of the two areas in the mammalian brain where adult neurogenesis occurs. Adult neurogenesis is well known to be involved in hippocampal physiological functions as well as pathophysiological conditions. Microtubules (MTs), providing intracellular transport, stability, and transmitting force, are indispensable for neurogenesis by facilitating cell division, migration, growth, and differentiation. Although there are several examples of MT‐stabilizing proteins regulating different aspects of adult neurogenesis, relatively little is known about the function of MT‐destabilizing proteins. Stathmin is such a MT‐destabilizing protein largely restricted to the CNS, and in contrast to its developmental family members, stathmin is also expressed at significant levels in the adult brain, notably in areas involved in adult neurogenesis. Here, we show an important role for stathmin during adult neurogenesis in the subgranular zone of the mouse hippocampus. After carefully mapping stathmin expression in the adult dentate gyrus (DG), we investigated its role in hippocampal neurogenesis making use of stathmin knockout mice. Although hippocampus development appears normal in these animals, different aspects of adult neurogenesis are affected. First, the number of proliferating Ki‐67+ cells is decreased in stathmin knockout mice, as well as the expression of the immature markers Nestin and PSA‐NCAM. However, newborn cells that do survive express more frequently the adult marker NeuN and have a more mature morphology. Furthermore, our data suggest that migration in the DG might be affected. We propose a model in which stathmin controls the transition from neuronal precursors to early postmitotic neurons.

Stem cells and neurogenesis in relation to Alzheimer's disease Models

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder associated with progressive cognitive decline and extensive neuropathology throughout the brain. Its main features include limited cell loss in selected subregions, generalized brain atrophy, and gradual accumulation of β-amyloid plaques and neurofibrillary tangles in several brain regions. One of the earliest and most prominently affected brain regions is the hippocampus, a brain structure involved in learning and memory that displays prominent cell loss in its CA1 subregion as well as abundant plaque and tangle pathology.