Current Alzheimer Research - Volume 8, Issue 6, 2011

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Pathological tau protein aggregates can be found in brain of patients with some of the neurodegenerative diseases collectively known as tauopathies, which include Alzheimer's disease (AD). Since tau post-translational modifications including phosphorylations, glycosylations, truncation and the subsequent aggregation in oligomers, paired helical filaments (PHFs) and neurofibrillary tangles (NFTs), correlate with cognitive impairment and neurodegeneration in AD, a pathogenic role for tau and its modifications has been raised. Here we summarize the current status of knowledge about tau modifications under pathologic conditions and the evidence supporting neurotoxic - or neuroprotective - roles of the diverse forms of modified and aggregated tau. Finally, we analyze the structural and functional tau alterations found in different tauopathies and how these modifications are related to the pathophysiologic mechanisms of neurodegeneration.

Neurodegenerative diseases termed Tauopathies, including Alzheimer disease, are characterized by the presence of intraneuronal neurofibrillary tangles (NFTs), composed by hyperphosphorylated protein Tau. Peptidyl-prolyl cis/trans isomerase Pin1 plays a pivotal role in the regulation of Tau phosphorylation/dephosphorylation state. Indeed, Pin1 specifically recognizes pThr231-Pro232 motif of Tau, catalyzes its isomerisation and, in dependence of the cellular environment, promotes its dephosphorylation by PP2A phosphatase: in the dephosphorylated state Tau is able to exert its physiological activity, promoting microtubules polymerization. However, Pin1 activity in Tauopathies in which Tau is mutated can be harmful, because the isomerase can accelerate progression of the disease. Taking into account the complexity of pathways in which Pin1, under a strict regulation, exerts its biological functions, this isomerase can be consider a promising target in the improvement and design of new therapies against Tauopathies.

Alzheimer disease (AD) is the most common cause of dementia in adults. Aberrant hyperphosphorylation of microtubule associated protein Tau and neurofilament-M/H is one of the pathological hallmarks of AD. Most of the therapeutic strategies for treating AD are based on the inhibition of protein kinases such as glycogen synthase kinase-3β, cyclin- dependent kinase 5, and other Tau kinases. Here, we focus on protein phosphatase 2A (PP2A) as a key player in AD. PP2A expression and activity are downregulated in AD brain, contributing to the aberrant phosphorylation of Tau and NF proteins in AD. Recent data published from our lab as well as others on PP2A deregulation in AD is reviewed. The role of peptidyl prolyl isomerase Pin1 in regulation of PP2A mediated neurodegeneration is further analyzed. Development of drugs for AD could be based on restoration of PP2A activity or targeting Pin1.

Alzheimer's disease (AD) is a neurodegenerative disorder histologically defined by the cerebral accumulation of amyloid deposits and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Loss of basal forebrain cholinergic neurons is another hallmark of the disease thought to contribute to the cognitive dysfunctions. To this date, the mechanisms underlying cholinergic neurons degeneration remain uncertain. The present study aimed to investigate the relationship between neurofibrillary degeneration and cholinergic defects in AD using THY-Tau22 transgenic mouse model exhibiting a major hippocampal AD-like tau pathology and hyperphosphorylated tau species in the septohippocampal pathway. Here, we report that at a time THY-Tau22 mice display strong reference memory alterations, the retrograde transport of fluorogold through the septohippocampal pathway is altered. This impairment is associated with a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum. Analysis of nerve growth factor (NGF) levels supports an accumulation of the mature neurotrophin in the hippocampus of THY-Tau22 mice, consistent with a decrease of its uptake or retrograde transport by cholinergic terminals. Finally, our data strongly support that tau pathology could be instrumental in the cholinergic neuronal loss observed in AD.

Mainstream thinking is dominated by the notion that the aggregation of specific proteins within neurons, and their subsequent formation into cytoplasmic and extracellular lesions, directly elicits neuronal dysfunction and death. Current dogma, for example, maintains that phosphorylated tau protein, the major component of neurofibrillary tangles, is a central mediator of disease pathogenesis. In this article, we challenge this classic notion by proposing that tau phosphorylation represents a compensatory response mounted by neurons against oxidative stress that serves a protective function. This concept provides a better understanding of the mechanisms underlying disease pathophysiology and also provides a window for therapeutic intervention.

Hyperphosphorylated tau is a cardinal feature of Alzheimer's disease (AD) pathology. The deregulation of kinases that phosphorylate tau can alter normal tau-related processes, including microtubule dynamics, growth cones, and axonal transport, and induce tau aggregation in paired helical filaments. Here we discuss the possible roles of the Abl family of tyrosine kinases, which are essential regulators of cytoskeleton cellular signaling cascades, in AD tau pathology and how the physiological roles of Abl kinases could be connected with the cytoskeletal alterations induced by Aβ aggregates and AD progression.

A major limitation in finding therapeutic solutions for Alzheimer's disease (AD) has been the lack of a reliable method for early diagnosis of this devastating disease. Besides the development of biomarkers in biological fluids of patients, the search for a pathology-specific neuroimaging tools is critical at the present stage in which almost 30 million people suffer this disease worldwide. Several interesting approaches have been developed, however their clinical impact has been low. One of the difficulties has been to find the proper molecular tracers to specifically tag pathognomonic lesions in AD brain, including not only amyloid aggregates but also filaments of the modified microtubule-associated protein tau. In this review, we analyze the evidence towards developing pathology-specific diagnostic tools for AD. We analyze the current evidence and clinical implications of new imaging technologies for AD, and how tau hypothesis and the amyloid cascade hypothesis will impact on these scientific efforts in the near future.

The aggregation and accumulation of the microtubule-associated protein (Tau) is a pathological hallmark of Alzheimer disease (AD) and many neurodegenerative diseases. For a long time research has focused on neurofibrillary tangles (NFTs) and other large meta-stable inclusions composed of aggregated hyperphosphorylated tau protein. The correlation between these structures and disease progression produced conflicting results; moreover, the mechanism of their formation remains poorly understood. Lately, the significance and toxicity of NFTs have been challenged and a new aggregated tau entity has emerged as the true pathogenic species in tauopathies and a possible mediator of Aβ toxicity in AD; specifically, aggregates of a size intermediate between monomers and NFTs the so-called tau oligomers. Tremendous efforts have been devoted toward the optimization of a safe vaccine for AD by targeting Aβ peptide; despite the disappointing results, these studies produced a wealth of useful knowledge, which should be considered in developing taubased immunotherapy. Herein, we discuss the evidence supporting the critical role of tau oligomers in AD, the potential and challenges for targeting them by immunotherapy as a novel approach for AD treatment.

Neurofibrillary tangles (NFTs) are one of the pathological hallmarks of Alzheimer's disease (AD) and are primarily composed of aggregates of hyperphosphorylated forms of the microtubule associated protein tau. It is likely that an imbalance of kinase and phosphatase activities leads to the abnormal phosphorylation of tau and subsequent aggregation. The wide ranging therapeutic approaches that are being developed include to inhibit tau kinases, to enhance phosphatase activity, to promote microtubule stability, and to reduce tau aggregate formation and/or enhance their clearance with small molecule drugs or by immunotherapeutic means. Most of these promising approaches are still in preclinical development whilst some have progressed to Phase II clinical trials. By pursuing these lines of study, a viable therapy for AD and related tauopathies may be obtained.

The anomalous aggregation of proteins into pathological filaments is a common feature of a many human diseases, often related to aging. In this context, neurodegenerative pathologies such as Alzheimer's disease (AD) account for a major part of these protein misfolding diseases. AD is characterized by pathological aggregation of two proteins, tau and Aβ-amyloid. The intracellular neurofibrillary tangles (NFTs) and neuropil threads consists of filaments of the modified microtubule-associated protein tau, while extracellular amyloid plaques consists of filaments of Aβ-peptide. It is noteworthy that tau oligomers with a prefilamentous structure appear to play a role at early stages of AD and tauopathies, but also in asymptomatic patients with Braak-stage I neuropathology, where clinical symptoms of AD and NFTs in frontal cortex are absent. This suggests that an increase in tau oligomers levels occurs before individuals manifest clinical symptoms of AD. NFTs are one of the hallmarks of Alzheimer disease and other tauphaties. These aggregates are thought to be toxic to neurons, either by causing some neurotoxic signalling defects or by obstructing the cell function. Factors contributing to accumulation of tau aggregates include the increased rate of protein misfolding, generation of amyloidogenic oligomers, underactivity of repair systems such as chaperones and ubiquitin-proteasome system, or a failure of energy supply and antioxidant defense mechanisms. There is not clear evidence if the aggregated tau or oligomers cause cellular damage, but on the basis of the emergent need to have an early and effective treatment, lowering the production or removal of these aggregates appears as a pathway toward alleviating the disease. In the context of some of most relevant reports, we analyze why tau protein seems to be an interesting target for AD treatment, and the importance to understand the pathways of tau. aggregation. This knowledge will allow us to identify and optimize potential inhibitors that interact with aggregated forms of tau and hyperphosphorylated tau before the formation of the NFTs, offering a possible therapeutic route for AD treatment.

Alzheimer's Disease (AD) physiopathology is not yet totally established. Nevertheless it is known that a metabolism dysfunction of the amyloid beta precursor protein (APP) and the abnormal tau protein phosphorylation lead to the formation of neuritic plaques and neurofibrillary tangles, respectively. These events finally drive to the clinical expression of dementia. Formally approved during the past decade, treatments for AD are lacking of an updating, being essentially symptomatic. Anticholinesterase agents have failed in providing a substantial improvement in the mental health condition of AD patients. On the other hand, antiamyloid strategies, have failed in their efficacy or security on their last development phases. In this context, tau represents a potential therapeutic target, by the action of drugs that diminish its aggregation, or acting by altering its phosphorylation or filaments formation. There is also anti-tau miscellaneous strategies such as normal microtubule-stabilizing agents. Thus, it might be possible that in a near future the neurodegenerative process could be stopped.

Background: At 3 years after diagnosis, the risk of Alzheimer disease (AD) for patients with mild cognitive impairment (MCI) is estimated to be 18% to 30%. To improve treatment of patients at high dementia risk there is a need for a better prediction of the risk for transition from MCI to AD. Olfactory deficits are a hypothetical predictor of conversion form MCI to AD. Furthermore, several studies point at volumetric reduction of medial temporal lobe structures as predictors of conversion form MCI to AD. The primary aim of this study was to evaluate whether investigations of odor deficits in MCI combined with neuropsychological tests and MRI examinations can improve prediction of the development of dementia. Methods: Changes in olfactory functions, cognitive functions, and volume of medial temporal lobe structures (hippocampus, parahippocampal gyrus, and amygdala) were evaluated in a 24-month follow-up study in 49 MCI patients and 33 controls. Results: In the MCI group, a prediction of strong cognitive functions deterioration based on poor performance in Olfactory Identification tests shows sensitivity of 57% and specificity of 88%. The test based on cognitive functions only shows a sensitivity of 44%, and 89%, respectively. Combined tests having a criteria of poor olfactory identification performance AND poor results of neuropsychological tests showed a sensitivity of 100% and specificity of 84%. Furthermore, correlation was found between the results of Olfactory Identification tests at baseline and deterioration of cognitive functions at follow up. Odor identification threshold did not appear to be a dementia predictor. A correlation of progress of cognitive function deterioration, odor identification deterioration, and decrease of volume of the hippocampus was also observed. Conclusions: Prediction of MCI to dementia conversion can be improved by supplementing the neuropsychological tests with odor identification tests. A follow up study of hippocampus volume reduction, OI performance and cognitive functions deterioration will further increase prediction accuracy.

Objective: Epidemiological studies suggest a relationship between midlife metabolism and old age cognition. We examined the effect of midlife BMI and related metabolic conditions on old age cognitive performance and whether there was evidence from direct causal pathways behind these associations in a large sample of Finnish twins. Design: Midlife variables of 2606 twin individuals were based on postal questionnaires and registry records. Old age cognitive status was measured by using a validated telephone interview. Results: Midlife BMI, cardiovascular disease, hypertension and diabetes were each associated with old age cognition when adjusted for sex, education, birth year and age at the interview. Similarly, overweight increased the risk for categories of mild impairment of cognitive function and likely dementia. Cardiovascular disease diminished the mean cognitive score also among discordant twin pairs (β-estimate=1.10, p value= 0.012). Weight gain more than 1.7 kg/m2 and loss more than 2 kg/m2 within an average of 5.6 years were associated with lower cognitive performance independently of BMI. An additive genetic correlation explained the association between BMI and old age cognition (rA=-0.12, 95% CI -0.21; -0.03), but adjustment for education led to loss of significance (rA=-0.06, 95% CI -0.16; 0.03). Conclusions: Midlife metabolic diseases, especially diabetes, are independently associated with impaired cognition in old age. Even a more subtle weight change than suggested previously was associated with lower old age cognition. There was evidence from direct causal pathway between cardiovascular disease and old age cognition, while the correlation between midlife BMI and old age cognition was explained mostly by genetic factors.