Current Topics in Medicinal Chemistry

ISSN: 1568-0266

Current Topics in Medicinal Chemistry
Volume 6, Number 6, 2006

Contents

Alzheimer’s Disease
Guest Editors: Shawn J. Stachel & Joseph P. Vacca


Editorial Pp. 551


Approaches to Palliative Therapies for Alzheimer’s Disease Pp. 553-568
Albert J. Robichaud
[Abstract]


Human β-Secretase (BACE) and BACE Inhibitors: Progress Report Pp. 569-578
Varghese John
[Abstract]


Tau Therapeutic Strategies for the Treatment of Alzheimer’s Disease Pp. 579-595
Ian Churcher
[Abstract]


The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in Alzheimer’s Disease Pp. 597-608
Susan Catalano, Elizabeth Chen-Dodson, Darrell A. Henze, Joseph Joyce, Grant A. Krafft and Gene G. Kinney
[Abstract]


Genetically Modified Mice Models for Alzheimer’s Disease Pp. 609-627
Sethu Sankaranarayanan
[Abstract]


The Role of MRI and PET/SPECT in Alzheimer’s Disease Pp.629-647
Alexandre Coimbra, Donald S. Williams and Eric D. Hostetler
[Abstract]




Abstracts

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Editorial

Alzheimer’s disease (AD) is a fatal degenerative disease of the brain that is rapidly becoming one of the largest unmet medical needs in the developed world. It is estimated that 4.5 million Americans currently have Alzheimer’s disease and that number is expected to rise dramatically due to the population bubble resulting from the baby boom and increased longevity from medical advances. Current national direct and indirect annual costs associated with treatment and care of Alzheimer’s patients is upwards of 100 billion dollars. Researchers over the past 20 years have uncovered a variety of genetic mutations that result in early onset AD or familial AD (FAD). However, our current understanding of genetic predisposition accounts for < 10% of AD cases, the majority of cases are sporadic in nature and the risk factor increases in an age dependent manner. It is generally recognized that β-amyloid plaques and neurofibrillary tangles are the key pathological features of the disease, although the specific roles of these agents in disease progression remain debatable.

Currently there are no therapies available to treat the progression or onset of Alzheimer’s disease. This issue of “Current Topic in Medicinal Chemistry” presents articles from six groups of researchers who are involved in various aspects of Alzheimer’s disease with the shared focus of finding effective treatments. The first review by Al Robichaud focuses on approaches to palliative therapies for Alzheimer’s disease. These agents are currently the ‘front-line’ treatment used to retard cognitive decline but are not directly disease-altering. Dr. Robichaud covers a diverse range of enzyme targets from muscarinic agonists to cannabinoid receptor ligands and summarizes their current developmental status.

The second review by Varghese John focuses on β-secretase (BACE). β-secretase is recognized as the rate limiting enzymatic event in the production of Aβ_40-42. The Aβ₄₂ peptide fragment is well documented as the major component of amyloid plaques. Dr. John describes the role of β-secretase in the amyloid cascade and the progress toward the development of BACE inhibitors. The next review by Ian Churcher describes the tau-related etiology of Alzheimer’s disease as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau. Hyperphosphorylation of the microtubule associated protein, tau, induces its aggregation to form neurofibrillar tangle (NFTs). Evidence suggests that these intracellular tangles are directly responsible for neuronal death. In the fourth review, Susan Catalano, Elizabeth Chen-Dodson, Darrel Henze, Joseph Joyce, Grant Krafft, and Gene Kinney discuss the role of amyloid-beta derived diffusible ligands (ADDLs) in Alzheimer’s disease. ADDLs are composed of soluble oligomers of Aβ₄₂ and have been implicated in neuronal cell death prior to plaque deposition. Vaccine and antibody-based therapeutic approaches aimed at lowering ADDL loads are covered.

The next two reviews focus on the development of biological and clinical methods for the assessment of promising therapeutic agents. Sethu Sankaranarayanan updates current views on amyloid and tau pathologies in mice models of AD. The development and limitations of these transgenic mice models and their effectiveness as human disease surrogates is described. Finally, Alexandre Coimbra, Donald Williams, and Eric Hostetler review the progress made in the fields of MRI and PET/SPECT imaging and their potential use as; a non-invasive tool to aid in early diagnosis, a method for assessing efficacy of disease-modifying agents, and a resource for monitoring progress in clinical evaluations.


Dr. Shawn J. Stachel
Merck & Co. Inc.
WP14-3 P.O. Box 4
770 Sumneytown Pike
West Point, PA 19486
USA
E-mail:shawn_stachel@merck.com


Dr. Joseph P. Vacca
Merck & Co. Inc.
WP14-3 P.O. Box 4
770 Sumneytown Pike
West Point, PA 19486
USA
E-mail: joe_vacca@merck.com


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Approaches to Palliative Therapies for Alzheimer’s Disease
Albert J. Robichaud

Alzheimer’s disease is a progressive neurodegenerative disease characterized by gradual and increasing loss of cognitive function and behavioral abnormalities. The formation of β-amyloid plaques and neurofibrillary tangles are recognized as the key pathologies of the disease. Changes in the levels of various key neurotransmitters has been noted in patients with Alzheimer’s disease and may represent the earliest biochemical casualty, preceding or signifying the onset of the disease. Over the last 20 years a number of approaches to the palliative treatment of Alzheimer’s disease have been scrutinized. The majority of effort has been focused on cognitive dysfunction, as this is the initial and key debilitating symptom of the disease. The identification and commercial development of the acetylcholinesterase inhibitors has, until recently, virtually dominated the field, and although efficacy has been demonstrated, the clinical results suggest alternate approaches are warranted. This review will highlight those palliative approaches that have focused on the improvement of learning and memory and not on the disease-modifying strategies of the β-amyloid, tau phosphorylation or other neurodegenerative hypotheses.


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Human β-Secretase (BACE) and BACE Inhibitors: Progress Report
Varghese John

A key step in the processing of the integral membrane protein APP, or Amyloid Precursor Protein is through the proteolytic cleavage by the enzyme β-Secretase (BACE). The proteolysis of APP by BACE, followed by subsequent C-terminal cleavage(s) by γ -secretase, results in the formation of the amyloid β (Aβ) peptide. The principal component of the neuritic plaque found in the brains of Alzheimer's Disease (AD) patients is Aβ which is a neurotoxic and highly aggregatory peptide segment of APP. The amyloid hypothesis holds that the neuronal dysfunction and clinical manifestation of AD is a consequence of the long term deposition and accumulation of 40-42 amino-acid long Aβ peptides, and that this process leads to the onset and progression of AD. Due to the apparent causal relationship between Aβ and AD, the so-called “secretases” that produce Aβ have been targeted for development of inhibitors that might serve as therapeutic agents for treatment of this dreaded, and ever more prevalent disease. Herein will be discussed our current understanding of BACE, its role in the formation of neuritic plaques and the known inhibitors of the enzyme.


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Tau Therapeutic Strategies for the Treatment of Alzheimer’s Disease
Ian Churcher

The two classical pathological hallmarks of Alzheimer’s disease are deposits of aggregated β-amyloid (Aβ) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Aβ pathology, an invariant trait of Alzheimer’s disease, disruption of tau processing is a necessary event in the neurotoxic cascade which eventually leads to neuronal death and subsequent dementia. Tau is a neuronal, microtubule-bound protein which becomes hyperphosphorylated as a result of an imbalance of the kinase and phosphatase activities which normally tightly regulate its phosphorylation. In addition to this pathogenic hyperphosphorylation, tau dissociates from microtubules and self-aggregates to form insoluble oligomers which progress to the macroscopic tangles evident in post mortem Alzheimer’s disease tissue. Subsequent toxicity may ensue either as a direct toxic effect of free tau oligomers or as a result of altered microtubule-dependent processes. In order to intervene pharmacologically in this disease process, much effort has been expended in order to identify and inhibit the kinases responsible for pathogenic hyperphosphorylation and many candidate kinases have been investigated including glycogen synthase kinase (GSK-3), cyclin-dependant kinase-5 (Cdk-5), MAPK family members (extracellular signal-regulated kinases 1 and 2 [Erk-1 and 2], MEK [MAP kinase kinase], c-Jun NH₂-terminal kinases (JNKs) and p38), casein kinase, calcium calmodulin-dependant kinase II (CaMK-II), microtubule affinity regulating kinase (MARK), protein kinase A (PKA / cAMP-dependant protein kinase) and others. Focus has also fallen upon the role of the phosphatases responsible for dephosphorylation of tau. This review will describe the tau-related etiology of Alzheimer’s disease and other tauopathies as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau.


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The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in Alzheimer’s Disease
Susan Catalano, Elizabeth Chen-Dodson, Darrell A. Henze, Joseph Joyce, Grant A. Krafft and Gene G. Kinney

The amyloid-β (Aβ) cascade hypothesis of Alzheimer’s disease (AD) has dominated research and subsequent therapeutic drug development for over two decades. Central to this hypothesis is the observation that Aβ is elevated in AD patients and that the disease is ultimately characterized by the central deposition of insoluble senile plaques. More recent evidence, however, suggests that the presence or absence of plaque is insufficient to fully account for the deleterious role of elevated Aβ in AD. Such studies support the basis for an alternate interpretation of the Aβ cascade hypothesis. Namely, that soluble oligomers of Aβ (i.e., ADDLs) accumulate and cause functional deficits prior to overt neuronal cell death or plaque deposition. Accordingly, the following review focuses on research describing the preparation and functional activity of ADDLs in vitro and in vivo. These studies provide the basis for an alternate, ADDL-based, view of the Aβ cascade hypothesis and accounts for the disconnect between plaque burden and cognitive deficits. Possible therapeutic approaches aimed at lowering ADDLs in AD patients are also considered.


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Genetically Modified Mice Models for Alzheimer’s Disease
Sethu Sankaranarayanan

Transgenic mice models for Alzheimer’s disease (AD) are essential to the understanding of disease pathophysiology, develop robust behavioral models and predict outcomes from pharmacological interventions. In the last 10 years, numerous mice models have been developed particularly focusing on the amyloid precursor protein-processing pathway and Tau pathology since brain amyloid deposits and Tau tangles are some of the primary neuropathological consequences of AD. Current views on the amyloid hypothesis and mice models relating to the role of soluble Aβ oligomers and intracellular Aβ in AD pathophysiology will be reviewed. Several novel transgenic mice models that have recently been developed and their potential impact on understanding disease pathogenesis will also be summarized.


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The Role of MRI and PET/SPECT in Alzheimer’s Disease
Alexandre Coimbra, Donald S. Williams and Eric D. Hostetler

Alzheimer’s disease (AD) is difficult to diagnose in its early stages, and even if detected early, there is no preventative treatment. Imaging modalities such as MRI, PET, and SPECT have the potential to contribute to both the diagnosis of Alzheimer’s disease, as well as assist in the search for more effective treatments. A number of AD-related biomarkers have been proposed and evaluated. The use of PET imaging to detect alterations in regional brain metabolism using [¹⁸F]FDG has enabled more sensitive and accurate early diagnosis of AD, especially in conjunction with traditional medical evaluation. Additionally, magnetic resonance imaging and spectroscopy provide a wide range of biomarkers that have been shown to correlate with the progression of AD. Some of these markers have been pursued in clinical trials. Progress has been made toward the evaluation of other more AD-specific biomarkers. However, many questions remain concerning the validity and sensitivity of these imaging biomarkers to aid in the assessment of potential new treatments, especially those related to increased levels of amyloid peptides in the brain.