Glycogen synthase kinase-3 (GSK-3) may play an important role in the pathogenesis of tauopathies and may represent a therapeutic target. This serine/threo-nine kinase exists in 2 isoforms (alpha and beta) encoded by 2 different genes, is most abundant in CNS in adults, and participates in many signaling cascades, including insulin/insulinlike growth factor 1 and Wnt signaling pathways. Increased GSK-3 activity may play a role in tauopathies because it can phosphorylate tau in vivo
in most sites that are found hyperphosphorylated in AD-tau [33
], but it also accumulates in pretangles [34
] and interacts with presenilin 1, which may result in increased activity of the enzyme. To study the consequences of sustained increased GSK-3 activity in adult tissues and to explore the therapeutic potential of GSK-3 inhibition, conditional transgenic mice that overexpress either wild-type GSK-3 or a dominant-negative form of the kinase have been generated. Mice with neuronal overexpression of wild-type GSK-3 show electrophysiologic abnormalities, histopathologic alterations (increased tau phosphorylation and neuronal loss without tau filament formation) [36
], and impaired spatial recognition [37
], consistent with the notion of increased GSK-3 activity participating in the etiology of AD and other tauopathies. Interestingly, the AD-like phenotype of Tet/GSK-3 mice fully reverts after restoration of normal GSK-3 activity in these conditional transgenic mice [38
], thus supporting the therapeutic potential of GSK-3 inhibitors. Besides, low-dose treatment with lithium (a GSK-3 inhibitor) convincingly prevents neuropathologic changes in mice with increased GSK-3 activity that also express FTDP-17 [39
]. However, GSK-3 knock-out mice die of liver failure in early embryonic development. Therefore, complete and early downregulation of GSK-3 might not be a useful approach. Regulatable Tet/DN-GSK-3 mice were developed to explore the efficacy and adverse effects of GSK-3 inhibition. Mice with decreased GSK-3 activity as a consequence of DN-GSK-3 expression showed increased incidence of neuronal apoptosis in brain regions involved in motor control such as striatum and cortex and concomitant deficit in motor coordination, thus warning of potential neurologic toxicity of GSK-3 pharmacologic inhibition beyond physiologic levels. Interestingly, the reversibility analysis in these mice also suggests that adverse effects are likely to subside if excessive GSK-3 inhibition is halted. Further analysis of these mice combined with transgenic models of tauopathies is expected to shed light on the therapeutic potential of pharmacologic GSK-3 inhibition in tauopathies.
The emphasis on kinases to explain the hyperphosphorylation of tau is a popular approach but may not be firmly supported by basic science data. Upregulation and downregulation of kinases in cells or mice yield contradictory results. GSK-3β has many targets, and inhibitors such as lithium have many targets as well. Moreover, hyperphosphorylation of tau (and other proteins) can be achieved simply by a slight drop in body temperature that shifts the balance of kinase and phosphatase activity [40
Mitochondrial dysfunction is thought to play an important role in the development of tau pathology. The Guadeloupe disease may serve as a good model for sporadic PSP [15
]. The consumption of Annonaceae plants is an identified risk factor for the disease. The toxic principle of Annonaceae plants may be mitochondrial toxins, such as isoquinolinic alkaloids and acetogenins. It has been shown in vitro
that Annonaceae plants are toxic for dopaminergic neurons [41
] by potent inhibition of complex I [42
]. After systemic administration, the compound enters the brain of experimental rodents and selectively destroys striatal and nigral neurons [43
]. Similar effects can be shown by the systemic administration of the complex I inhibitor rotenone, a compound used, amongst other things, for eradicating unwanted fish in the tropics [44
]. In addition, an accumulation of hyperphosphorylated tau and the tau accumulation in neuronal and glial cells were observed [45
]. Because this observation is complementary to evidence of mitochondrial dysfunction in PSP [46
], two pilot trials, one with coenzyme Q10 and another with creatine, pyruvate, and niacinamide, in PSP have been proposed.
Chronic inflammation may play a major role in the pathogenesis of tauopathies; inflammation may drive the disease process through self-attack on viable tissue. McGeer and McGeer [47
] introduced the term autotoxic diseases
(to be distinguished from autoimmune diseases
) and considered tauopathy a typical example of autotoxic disease. Activated microglia mediate such toxicity by producing harmful concentrations of free radicals, glutamate, cytokines, complement proteins, and prostaglandins. Retrospective studies [48
] have reported findings consistent with the concept that nonsteroidal antiphlogistics may have disease-modifying potential.
Based on our current understanding of the patho-physiology and pathobiochemistry of tauopathies, the pharmacologic modification of tau hyperphosphorylation, tau conformation, tau fragmentation, and tau aggregation may be considered as potential therapeutic targets in tauopathies. Since tau hyperphosphorylation leads to destabilization of microtubules (“loss of function”), stabilizing drugs (for example, paclitaxel) have been used in tauopathy models and were shown to be effective in preventing Aβ-induced neurodegeneration and even to reverse fast axonal transport deficits [50
]. tau hyperphosphorylation is a putative gain of the functional mechanism by which paired helical filaments are formed. To influence this potentially toxic mechanism, tau kinase inhibition may be the pharmacologic target to modify the disease process, as stated above regarding GSK-3. However, understanding the redundancy and the sequential activation of kinases may be necessary before these compounds can be tested. It has been shown recently that a small molecular inhibitor of kinases has a beneficial effect in the P301L mouse model [51
], showing that this concept can be proven in principle. Most interesting for potential human trials is the demonstration that lithium as well as specific GSK-3β inhibitors blocks tau pathology [39
]. Activation of tau phosphatase as a therapeutic mechanism, however, may have competing effects and requires better understanding. Another therapeutic path may be use of the prolyl isomerase Pin1 to restore the function of tau by altering its conformation. An understanding of the normal function of Pin1 is only beginning; deletion of the gene encoding Pin1 leads to a neurologic phenotype with tau hyperphosphorylation, tau filament formation, and neuronal degeneration [53
]. Inhibition of tau proteolysis may prevent neurotoxicity [54
] and tau aggregation [55
]. Caspases and other cytosolic proteases are suspected of being involved in the proteolytic processing of tau. Finally, tau aggregation is accelerated by the presence of polyanions (e.g. RNA, acidic peptides, or fatty acid micelles). Several classes of compounds were shown to inhibit tau aggregation, such as anthraquinones, phenothiazines, benzothiazoles, and polyphenols [56
]. Such compounds are able to relieve the aggregation-dependent toxicity of tau in cell models. An immunotherapeutic approach to brain diseases with aggregating proteins has shown promise [57
], although opposite experiences have also been reported [58
]. includes information on different therapeutic targets that may be used in drug development and treatment.
Possible therapeutic targets in tauopathies
The path of drug discovery leads from target validation to in vitro assay development (yeast, cell cultures), compound library design, and screening to in vivo experimental trials for efficacy and toxicity (Drosophila melanogaster and rodents), and finally from transgenic animal models to human applications. A synopsis of transgenic models is presented in .
Synopsis of transgenic models for tauopathies
Methods for comprehensive clinical assessment of PSP are highly relevant, with a special focus on end-points for therapeutic interventions, i.e. existing scales like the Unified Parkinson Disease Rating Scale Part III, Addenbrook's Cognitive Examination, and newly devised disease-specific scales such as the Golbe PSP scale [82
] and future ‘composite’ scales such as the NNIPPS scale. Functional milestones such as falls, dysphagia, and percutaneous endoscopic gastrostomy insertion may serve as end-points and are all consistently related to survival [4
]. For the purpose of a therapeutic trial, it was postulated that:
- a large geographic area or a multicenter trial is required;
- early modification of the disease will be difficult because nonspecific features would create noise; and
- hard end-points may be death or functional measures such as motor milestones.
In a systematic PubMed search, van Balken and Litvan [83
] found 96 reports on clinical trials describing 842 PSP patients. Taken together, the results were generally disappointing; only mild and transient benefits were reported in studies with multiple methodologic problems. van Balken and Litvan pointed out that future trials should have more rigorous methods, should be randomized, double-blind, and placebo-controlled, and should use only validated outcome measures. It is hoped that experimental trials in tau animal models will accelerate research in humans.
Given the variability of the clinical picture and the low prevalence of tauopathies, knowledge on the spectrum of the diseases must include rare disease forms and their early clinical differentiation (CBD, PSP-parkinsonism, and other rare forms dominated by apraxias or frontal dementias). The importance of performing autopsies on as many cases as possible cannot be overemphasized. Current clinical criteria are imperfect, and they are complicated by the frequency of overlapping pathologies. Most importantly, the causation of the syndromes described remains unknown, and only through further studies of diseased tissue can definitive answers be obtained. In addition, a database must be developed that reliably reflects the natural history of the diseases. The NNIPPS study is a natural history study that is attempting to establish such a database using early diagnostic criteria. An indirect excitotoxic pathway resulting from mitochondrial failure has been proposed to be a part of pathogenesis of cell damage in PSP [15
]. Therefore, the NNIPPS investigators used the putative glutamate release blocker riluzole as a disease-modifying agent in PSP, but the therapeutic study failed to show a beneficial effect of the drug. However, the 3-year longitudinal assessment of the clinical phenotype in 767 patients with MSA or PSP will presumably be a way to identify more neuroprotective compounds in the future. The NNIPPS study has shown that these early inclusion criteria are predictive for neuropathologic classification. In addition, the natural history data will enable precise power calculations for functional measures and the end-point, survival. The need for further studies of symptomatic treatment approaches to PSP, in particular for the treatment and prevention of falls, dysphagia, and sepsis, is also important [2
To test the clinical efficacy of potential disease-modifying compounds, a network of investigators interested in these ‘orphan’ diseases has the potential to expedite identification of novel therapies. Such a network may be particularly relevant for disorders affecting patients dispersed over large geographic areas. Investigator-initiated networks facilitate the development and harmonization of assessment tools and should provide data-capture systems for affordable human trials in these rare diseases. To achieve this goal of conducting human trials, clinicians and basic scientists as well as patient organizations should collaborate. The aims of the lay organizations are 2-fold: first, they want to be an interface between researchers and patients, and second, they attempt to provide patients insight into daily life problems and current scientific views of the disease.
In Europe, the Committee for Orphan Medicinal Products of the European Medicines Agency is responsible for opinions on orphan designation, provides incentives for the development of medicines for rare diseases, advises the European commission on orphan policy, and seeks international cooperation for rare diseases. European criteria for orphan designation include rarity (≤5 affected of 10 000 population), seriousness of the condition (life-threatening or disabling), and the lack of satisfactory methods of treatment. Up to February 2008, 783 orphan applications had been submitted to the European Medicines Agency; 541 were positive, amongst which 365 (67%) were based on significant benefit and 80% of those were based on potential improved efficacy.