Carlo Ballatore

Bio: Carlo Ballatore is an academic researcher from University of Montana. The author has contributed to research in topics: Tau protein & Tauopathy. The author has an hindex of 32, co-authored 88 publications receiving 5045 citations. Previous affiliations of Carlo Ballatore include National Institutes of Health & Cardiff University.

Tau-mediated neurodegeneration in Alzheimer's disease and related disorders.

Abstract: Advances in our understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease (AD) and related tauopathies, which are characterized by prominent CNS accumulations of fibrillar tau inclusions, are rapidly moving this previously underexplored disease pathway to centre stage for disease-modifying drug discovery efforts. However, controversies abound concerning whether or not the deleterious effects of tau pathologies result from toxic gains-of-function by pathological tau or from critical losses of normal tau function in the disease state. This Review summarizes the most recent advances in our knowledge of the mechanisms of tau-mediated neurodegeneration to forge an integrated concept of those tau-linked disease processes that drive the onset and progression of AD and related tauopathies.

The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice

Abstract: Neurodegenerative tauopathies, such as Alzheimer's disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a transgenic model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing.

Carboxylic Acid (Bio)Isosteres in Drug Design

Abstract: The carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also be responsible for significant drawbacks, including metabolic instability, toxicity, as well as limited passive diffusion across biological membranes. To avoid some of these shortcomings while retaining the desired attributes of the carboxylic acid moiety, medicinal chemists often investigate the use of carboxylic acid (bio)isosteres. The same type of strategy can also be effective for a variety other purposes, for example, to increase the selectivity of a biologically active compound or to create new intellectual property. Several carboxylic acid isosteres have been reported, however, the outcome of any isosteric replacement cannot be readily predicted as this strategy is generally found to be dependent upon the particular context (i.e., the characteristic properties of the drug and the drug–target). As a result, screening of a panel of isosteres is typically required. In this context, the discovery and development of novel carboxylic acid surrogates that could complement the existing palette of isosteres remains an important area of research. The goal of this Minireview is to provide an overview of the most commonly employed carboxylic acid (bio)isosteres and to present representative examples demonstrating the use and utility of each isostere in drug design.

Epothilone D Improves Microtubule Density, Axonal Integrity, and Cognition in a Transgenic Mouse Model of Tauopathy

Abstract: Neurons in the brains of those with Alzheimer's disease (AD) and many frontotemporal dementias (FTDs) contain neurofibrillary tangles comprised of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs), and tau misfolding could lead to a loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, a possible therapeutic strategy for AD and related “tauopathies” is treatment with a MT-stabilizing anti-cancer drug such as paclitaxel. However, paclitaxel and related taxanes have poor blood–brain barrier permeability and thus are unsuitable for diseases of the brain. We demonstrate here that the MT-stabilizing agent, epothilone D (EpoD), is brain-penetrant and we subsequently evaluated whether EpoD can compensate for tau loss-of-function in PS19 tau transgenic mice that develop forebrain tau inclusions, axonal degeneration and MT deficits. Treatment of 3-month-old male PS19 mice with low doses of EpoD once weekly for a 3 month period significantly improved CNS MT density and axonal integrity without inducing notable side-effects. Moreover, EpoD treatment reduced cognitive deficits that were observed in the PS19 mice. These results suggest that certain brain-penetrant MT-stabilizing agents might provide a viable therapeutic strategy for the treatment of AD and FTDs.

Microtubule stabilizing agents as potential treatment for Alzheimer's disease and related neurodegenerative tauopathies.

Abstract: The microtubule (MT) associated protein tau, which is highly expressed in the axons of neurons, is an endogenous MT-stabilizing agent that plays an important role in axonal transport. Loss of MT-stabilizing tau function, caused by misfolding, hyperphosphorylation, and sequestration of tau into insoluble aggregates, leads to axonal transport deficits with neuropathological consequences. Several in vitro and preclinical in vivo studies have shown that MT-stabilizing drugs can be utilized to compensate for the loss of tau function and to maintain/restore effective axonal transport. These findings indicate that MT-stabilizing compounds hold considerable promise for the treatment of Alzheimer disease and related tauopathies. The present article provides a synopsis of the key findings demonstrating the therapeutic potential of MT-stabilizing drugs in the context of neurodegenerative tauopathies, as well as an overview of the different classes of MT-stabilizing compounds.

Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade

Abstract: Summary Currently available evidence strongly supports the position that the initiating event in Alzheimer's disease (AD) is related to abnormal processing of β-amyloid (Aβ) peptide, ultimately leading to formation of Aβ plaques in the brain. This process occurs while individuals are still cognitively normal. Biomarkers of brain β-amyloidosis are reductions in CSF Aβ 42 and increased amyloid PET tracer retention. After a lag period, which varies from patient to patient, neuronal dysfunction and neurodegeneration become the dominant pathological processes. Biomarkers of neuronal injury and neurodegeneration are increased CSF tau and structural MRI measures of cerebral atrophy. Neurodegeneration is accompanied by synaptic dysfunction, which is indicated by decreased fluorodeoxyglucose uptake on PET. We propose a model that relates disease stage to AD biomarkers in which Aβ biomarkers become abnormal first, before neurodegenerative biomarkers and cognitive symptoms, and neurodegenerative biomarkers become abnormal later, and correlate with clinical symptom severity.

Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers.

Abstract: Summary In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.

Tau-mediated neurodegeneration in Alzheimer's disease and related disorders.

Abstract: Advances in our understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease (AD) and related tauopathies, which are characterized by prominent CNS accumulations of fibrillar tau inclusions, are rapidly moving this previously underexplored disease pathway to centre stage for disease-modifying drug discovery efforts. However, controversies abound concerning whether or not the deleterious effects of tau pathologies result from toxic gains-of-function by pathological tau or from critical losses of normal tau function in the disease state. This Review summarizes the most recent advances in our knowledge of the mechanisms of tau-mediated neurodegeneration to forge an integrated concept of those tau-linked disease processes that drive the onset and progression of AD and related tauopathies.