Avila, Jesús, José J. Lucas, Mar Pérez, and Félix Hernández. Role of Tau Protein in Both Physiological and Pathological Conditions. Physiol Rev 84: 361–384, 2004; 10.1152/physrev.00024.2003.—The morphology of a neuron is determined by its cytoskeletal scaffolding. Thus proteins that associate with the principal cytoskeletal compo-nents such as the microtubules have a strong influence on both the morphology and physiology of neurons. Tau is a microtubule-associated protein that stabilizes neuronal microtubules under normal physiological conditions. However, in certain pathological situations, tau protein may undergo modifications, mainly through phosphorylation, that can result in the generation of aberrant aggregates that are toxic to neurons. This process occurs in a number of neurological disorders collectively known as tauopathies, the most commonly recognized of which is Alzheimer's disease. The purpose of this review is to define the role of tau protein under normal physiological conditions and to highlight the role of the protein in different tauopathies.

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Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC₅₀ = 104 ± 27 nM), in an ATP-competitive manner (K_i = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC₅₀ > 100 μM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3β protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by β-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.

Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants—TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, and HLA-DRB5-HLA-DRB1—potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish in vivo and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal–spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker–drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.

Deregulation of glycogen synthase kinase‐3 (GSK‐3) activity in neurones has been postulated as a key feature in Alzheimer's disease (AD) pathogenesis. This was further supported by our recent characterization of transgenic mice that conditionally over‐express GSK‐3β in hippocampal and cortical neurones. These mice, designated Tet/GSK‐3β, showed many of the biochemical and cellular aspects of AD neuropathology such as tau hyperphosphorylation and somatodendritic localization, decreased nuclear β‐catenin, neuronal death and reactive gliosis. Tet/GSK‐3β mice, however, did not show tau filament formation up to the latest tested age of 3 months at least. Here we report spatial learning deficits of Tet/GSK‐3β mice in the Morris water maze. In parallel, we also measured the increase in GSK‐3 activity while further exploring the possibility of tau filament formation in aged mice. We found a significant increase in GSK‐3 activity in the hippocampus of Tet/GSK‐3β mice whereas no tau fibrils could be found even in very old mice. These data reinforce the hypothesis of GSK‐3 deregulation in AD pathogenesis, and suggest that Tet/GSK‐3β mice can be used as an AD model and, most remarkably, can be used to test the therapeutic potential of the selective GSK‐3 inhibitors that are currently under development. Additionally, these experiments suggest that destabilization of microtubules and alteration of intracellular metabolic pathways contribute to AD pathogenesis independent of toxicity triggered by the aberrant tau deposits.

Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed serine/threonine kinase that plays a key role in the pathogenesis of Alzheimer's disease (AD). GSK3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in paired h