Two Wnt Pathways Control Adult Neurogenesis
Simon T. Schafer, Jinju Han, Monique Pena, Oliver von Bohlen und Halbach, Jörg Peters, et al.
(see pages 4983–4998)
Wnts are secreted proteins that regulate numerous aspects of ontogeny, from stem cell proliferation through organ morphogenesis. In the developing nervous system, neural tube patterning, stem cell proliferation, and neural fate specification are regulated by the so-called canonical Wnt pathway, in which Wnts bind to receptor complexes composed of Frizzled (FZD) and LRP6 and activate a signaling cascade that leads to translocation of β-catenin to the nucleus, resulting in activation of transcription factors. Later in development, a different set of Wnts, acting through different FZD receptors, regulate axon and dendritic growth and synaptogenesis independently of β-catenin. This noncanoncial pathway resembles the planar cell polarity pathway, involving activation of JNK and c-JUN kinases, which in turn regulate cytoskeletal dynamics. Notably, the adaptor protein ATP6AP2 is involved in both canonical and noncanonical Wnt signaling.
Knocking down FZD3, a receptor that activates noncanonical Wnt signaling (right), causes the dendrites of newborn dentate granule cells (green) to be shorter and improperly oriented compared to controls (left). See the article by Schafer et al. for details.
In the adult dentate gyrus, Wnt3A binds to canonical FZD/LRP6 receptors on neural stem cells, leading to activation of transcription factors involved in neuronal differentiation. Schafer et al. now demonstrate that the noncanonical Wnt signaling pathway plays a role later in adult neurogenesis. As mouse adult hippocampal progenitor cells differentiated into neuroblasts in vitro, expression of Fzd4 and Lrp6 decreased, while expression of Atp6ap2, Fzd3, and Fzd6 increased. Consistent with the switch in Wnt receptor expression, WNT3A activated canonical signaling pathways exclusively in proliferating progenitors, whereas WNT5A activated noncanonical signaling exclusively in differentiating neurons.
Knocking down ATP6AP2 reduced the effects of Wnts at both developmental stages. Moreover, knocking down ATP6AP2 in adult dentate gyrus in vivo not only reduced neurogenesis, but also affected morphogenesis: those neurons that were generated migrated further than normal, and their dendrites were misoriented and underdeveloped. Importantly, knocking down the canonical-pathway coreceptor LRP6 reduced neurogenesis without affecting dendritic morphology, whereas knocking down the noncanonical-pathway receptor FZD3 altered neuronal migration and dendritic development without affecting neurogenesis.
These results indicate that as adult neurogenesis proceeds, neuroblasts stop responding to canonical Wnt ligands and instead begin to respond to noncanonical ligands. This switch likely ensures that cells at different stages of neurogenesis respond appropriately to diffusible environmental cues, despite being confined to a relatively small area.
Reducing Tau Reduces Soluble β-Amyloid in AD Model
Diana L. Castillo-Carranza, Marcos J. Guerrero-Muñoz, Urmi Sengupta, Caterina Hernandez, Alan D.T. Barrett, et al.
(see pages 4857–4868)
The two main neuropathological hallmarks of Alzheimer's disease (AD) are extracellular plaques containing aggregated β-amyloid peptides (Aβ) and intraneuronal neurofibrillary tangles composed of abnormally phosphorylated tau protein. The relationship between these two pathologies and their relative contributions to synaptic dysfunction, neurodegeneration, and cognitive decline are unclear. Evidence suggests that AD can be triggered by excessive generation of long (≥42 amino acids) Aβ peptides, which are prone to aggregation and can initiate a pathological cascade that includes hyperphosphorylation and aggregation of tau. Importantly, however, AD-causing mutations that lead to the generation of excessive Aβ do not cause synaptic loss, neurodegeneration, or cognitive deficits in mice that are also deficient in tau, suggesting that tau is required for Aβ toxicity. Reducing tau levels may therefore be neuroprotective in those prone to AD. Castillo-Carranza et al. provide compelling evidence that this is the case.
Castillo-Carranza et al. injected antibodies targeting tau oligomers into 14-month-old transgenic mice (Tg2576) that expressed an AD-linked form of amyloid precursor protein (from which Aβ is generated). Two weeks after the injection, mice not only had lower levels of oligomeric tau than controls, but also exhibited improved performance on two cognitive tasks: novel object recognition and contextual fear conditioning. These effects were associated with an increase in the proportion of mature, mushroom-shaped dendritic spines and a decrease in thin spines. Interestingly, anti-tau antibodies also reduced the levels of soluble Aβ oligomers, particularly the most toxic dodecamers, while increasing the number of trimers, suggesting that tau aggregates affect Aβ oligomerization and deposition. This may occur partly through direct interactions between the two types of oligomers, because Aβ was coimmunoprecipitated with tau oligomers. Importantly, anti-tau antibodies also enlarged amyloid plaques, consistent with mounting evidence that these plaques protect neurons from the toxic effects of soluble Aβ oligomers.
These data indicate that immunotherapy targeting tau oligomers might be an effective treatment for AD. Notably, the effects occurred with a single peripheral injection of antibodies at an age when neuropathology was already present, suggesting that unlike most other therapies, targeting tau oligomers may reverse, rather than just slow, the pathological process.
