Current Alzheimer Research - Volume 2, Issue 1, 2005

Hyperphosphorylation and accumulation of tau in neurons (and glial cells) is one the main pathologic hallmarks in Alzheimer's disease (AD) and other tauopathies, including Pick's disease (PiD), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease and familial frontotemporal dementia and parkinsonism linked to chromosome 17 due to mutations in the tau gene (FTDP-17-tau). Hyperphosphorylation of tau is regulated by several kinases that phosphorylate specific sites of tau in vitro. GSK-3-immunoprecipitated sarcosyl-insoluble fractions in AD have the capacity to phosphorylate recombinant tau. In addition, GSK-3 phosphorylated at Ser9, that inactivates GSK-3, is found in the majority of neurons with neurofibrillary tangles and dystrophic neurites of senile plaques in AD, and in Pick bodies and other phospho-tau-containing neurons and glial cells in other tauopathies. Increased expression of active kinases, including stress-activated kinase, c-Jun N-terminal kinase (SAPK / JNK) and kinase p38 has been found in brain homogenates in all the tauopathies. Strong active SAPK / JNK and p38 immunoreactivity has been observed restricted to neurons and glial cells containing hyperphosphorylated tau, as well as in dystrophic neurites of senile plaques in AD. Moreover, SAPK / JNK- and p38-immunoprecipitated sub-cellular fractions enriched in abnormal hyperphosphorylated tau have the capacity to phosphorylate recombinant tau and c-Jun and ATF-2 which are specific substrates of SAPK / JNK and p38 in AD and PiD. Interestingly, increased expression of phosphorylated (active) SAPK / JNK and p38 and hyperphosphorylated tau containing neurites have been observed around βA4 amyloid deposits in the brain of transgenic mice (Tg 2576) carrying the double APP Swedish mutation. These findings suggest that bA4 amyloid has the capacity to trigger the activation of stress kinases which, in turn, phosphorylate tau in neurites surrounding amyloid deposits. Complementary findings have been reported from the autopsy of two AD patients who participated in an amyloid-b immunization trial and died during the course of immunization-induced encephalitis. The neuropathological examination of the brain showed massive focal reduction of amyloid plaques but not of neurofibrillary degeneration. Activation of SAPK / JNK and p38 were reduced together with decreased tau hyperphosphorylation of aberrant neurites in association with decreased amyloid plaques in both Tg2576 mice and human brains. These findings support the amyloid cascade hypothesis of tau phosphorylation mediated by stress kinases in dystrophic neurites of senile plaques but not that of neurofibrillary tangles and neuropil threads in AD.

A conspicuous feature shared by Alzheimer's disease as well as a variety of highly prevalent, clinically unrelated neurodegenerative disorders is the occurrence of protein aggregates both intra- and extracellularly. Most of these conditions are characterized at autopsy by the presence of such deposits, typically of fibrillar structure and accompanying extensive neuronal cell loss, displaying a selective brain distribution. The recently discovered similarities of a number of these aggregates with a novel type of experimentally induced protein deposit, formed as a general response to discrepancies in protein turnover and designated the “aggresome”, has prompted speculations about the involvement of the ubiquitin-proteasome system in a process fundamental to neurodegeneration. Consistent with this view, protein aggregates have been regarded in a pathogenic connotation, with most aspects of neurologic pathogenesis being largely attributed to their presence in nerve tissues. However, the neurotoxicity of protein aggregates remains ambiguous as direct evidence substantiating it have long remained elusive. A convergence of evidence now support the notion that the actual culprits might comprise the oligomeric, non-fibrillar intermediates that arise early during the aggregation process, termed protofibrils and that the fibrillar end-stage aggregates themselves might actually serve a neuroprotective function. These intermediates ostensibly resolve many puzzling aspects of neurodegeneration and there is evidence that neurotoxicity is one key operational property they may possess. The above attest to the fact that protein aggregation remains a complex issue with a role far more enigmatic than originally thought but nonetheless important for the understanding of the pathological basis of neurodegenerative disorders.

The primary function of the renin-angiotensin system (RAS) is to maintain fluid homeostasis and regulate blood pressure. Several components of the RAS, namely angiotensinogen, angiotensin converting enzyme, angiotensin II and their receptors, are found in the CNS suggesting the possibility of a localized RAS in the brain. Cognitively disabling neurodegenerative disorders such as Alzheimer's disease or vascular dementia show vascular lesions, and the brain RAS has been suggested to contribute to the disease process. The aim of this brief review is to summarize the current state of research in this field with emphasis on RAS-related alterations during the course of neurodegenerative disorders.

Alzheimer's disease (AD) has been associated with aggregation of β-amyloid peptide (Aβ) and cell death in the brain. Using various models, such as the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster and the mouse Mus musculus, investigators have attempted to imitate the pathology process of AD for better understanding of the cellular mechanisms and for possible therapeutic intervention. Among many in vitro and in vivo models of AD, transgenic C. elegans expressing human Aβ has shown its own advantages. The transgenic C. elegans model have been used in studying AD due to its short life span, facility to maintain, ability to develop muscle-associated deposits reactive to amyloid-specific dyes and the concomitant progressive paralysis phenotype. Moreover, the transgenic C. elegans exhibits increased levels of reactive oxygen species (ROS) and protein carbonyls, similar to those observed in AD patients, supporting the current theory on Aβ-induced oxidative stress and subsequent neurodegeneration in AD. DNA microarray assays of the worm demonstrated several stress-related genes being upregulated, particularly two genes homologous to human αB-crystallin and tumor necrosis factor-related protein, which were also upregulated in postmortem AD brain. Studies in our laboratory along with others suggest that the transgenic C. elegans model is a suitable in vivo model to relate Aβ-expression with its toxicity, which may underlie AD pathology. It may also be used as a tool for pharmacological evaluation of novel therapeutic agents.

As the spectrum of therapeutic options broadens, the possibility of an early and accurate diagnosis of Alzheimer's disease (AD), or even isolation of a group at high risk of subsequent cognitive decline, is focusing widespread attention. Therefore, biological markers or risk factors of AD are highly desirable. In this work, we give an overview of the most extensively studied AD biomarkers, namely beta-amyloid, tau protein, and phosphorylated tau-protein, alone or in combination. Moreover, we describe the role of inflammatory markers (cytokines, acute phase proteins), oxidative stress markers (isoprostanes, 8-hydroxyguanine, 3-nitrotyrosine, plasma antioxidants, redox transition metals), homocysteine and related vitamins, cholesterol and 24S-hydroxycholesterol in the diagnostic process or prediction of AD. We briefly review less popular, though promising markers of AD - markers of apoptosis, neuronal thread protein, acetyl- and butyrylcholinesterase, sulfatide, kallikreins, matrix-degrading metalloproteinases, and novel isoforms of beta-amyloid and tau. Finally, we discuss the clinical applicability of AD-related biological markers.

Lipids have many important yet distinct functions in cellular homeostasis such as forming an impermeable barrier separating intracellular and extracellular compartments, providing a matrix for the appropriate interactions of membrane-associated proteins, and serving as storage reservoirs for biologically active second messengers. Alterations in cellular lipids may therefore result in abnormal cellular functions. This review summarizes the results from the examination of lipid alterations in Alzheimer's disease (AD). In addition to the effects of cholesterol on AD, substantial depletions of plasmalogen and sulfatide as well as dramatic increases in ceramide are specifically manifested at the earliest clinically recognizable stage of AD. The potential mechanism(s) underlying these changes and the potential consequences of these changes in neuronal function and in AD development are also discussed. Collectively, this review will provide an overview of the lipid alterations in Alzheimer's disease and the relationship of these lipid alterations with the development of AD pathogenesis.

It has long been recognised that Alzheimer's disease (AD) patients present an irreversible decline of cognitive functions as consequence of cell deterioration in the forebrain cholinergic projection system (FCPS), particularly, in a structure called nucleus basalis of Meynert (nbM). The reduction of the number of cholinergic cells in the FCPS disrupts not just its functions and direct connexions but also the modulation of other systems causing interference in several aspects of behavioural performance including arousal, attention, learning and emotion. It is also common knowledge that AD is an untreatable degenerative disease with very few temporary and palliative drug therapies. Neural stem cell (NSC) grafts present a potential and innovative strategy for the treatment of many disorders of the central nervous system including AD, with the possibility of providing a more permanent remedy than present drug treatments. After grafting, these cells have the capacity to migrate to lesioned regions of the brain and differentiate into the necessary type of cells that are lacking in the diseased brain, supplying it with the cell population needed to promote recovery. The present article aims to review the main aspects of Alzheimer's disease and to explore the use of neural stem cells grafts as alternative treatment for the consequent functional deterioration.

Due to an oversight, the figure caption on the Contents page of Current Alzheimer Research, Volume 1, Number 4 was wrongly published. The corrected caption is reproduced as follows: The figure shown on the front cover of this journal was taken from the article entitled Amyloid b-Peptide: The Inside Story (pp. 231-239) by Bertrand P. Tseng, Masashi Kitazawa and Frank M. LaFerla. The slide shows a proposed model of the effects of intraneuronal amyloid b-peptide (Ab) on key neurobiological phenomena. Ab is proteolytically derived from the large Ab precursor protein (APP). Mutations in the presenilin genes also affect the formation of intracellular Ab which exists as monomers, oligomers or fibrils. The potential pathophysiolgical contribution of intracellular Ab accumulation includes synaptic dysfunction, proteasome dysfunction, calcium dyshomeostasis and tau hyperphosphorylation. The cell membrane is shown to separate extracellular and intracellular compartments.