Volume 1, Numbers 4-5, Guest Editor: James Geddes, November 1999

Pages 197-201
William B. Grant
Dietary Links to Alzheimer's Disease
Summary: With the republication of Grant [1997], the first paper providing epidemiologic evidence linking diet to the development of Alzheimer’s disease (AD), it is an appropriate time to review the findings and hypotheses therein in light of the subsequent literature.  The main findings, that dietary fat and energy in old age are high risk factors, while fish and cereals are risk-reduction factors, have been supported in various recent epidemiologic studies.  Diet contributes to the development of AD through modulating oxidative stress and inflammation, which is also linked to oxidative stress, but may also arise from series 2 prostaglandins.  Thus, as one ages, dietary modifications and additional supplements designed to reduce free radical production and inflammation provide a significant measure of reduction in risk for the development of AD.

Pages 203-206
Mark A. Smith, Grace J. Petot, and George Perry
Commentary: Diet and Oxidative Stress: A Novel Synthesis of Epidemiological Data on Alzheimer's Disease
Summary: In an innovative synthesis, William B. Grant links Alzheimer’s disease to diet by combining the prevalence of Alzheimer’s disease in several countries with a meta-analysis of community-based studies of diet [Grant, 1997]. A positive relationship between caloric, as well as fat, intake and the prevalence of Alzheimer’s disease is demonstrated. These findings link Alzheimer’s disease to diet in a more general sense than previous studies that focused instead on specific dietary components such as consumption of brain, raw meat, seafood, alcohol, coffee or vitamin supplements. These latter studies usually had the single goal of determining whether food-borne pathogens or toxins might be implicated, rather than focusing on foods as a source of nutrients.

Pages 207-219
Andrea Wevers and Hannsjörg Schröder
Nicotinic Acetylcholine Receptors in Alzheimer's Disease
Summary: Nicotinic cholinoceptive dysfunction associated with cognitive impairment is a leading neurochemical feature of Alzheimer’s disease. Therefore, nicotinic acetylcholine receptors have attracted considerable interest as potential therapeutic targets. The deficit of nicotine binding sites in Alzheimer's disease may be related to alterations of nicotinic receptor synthesis on the levels of (i) transcription, (ii) translation and post-translational modifications, (iii) receptor transport and turnover, including membrane insertion. Current approaches aim at the elucidation of molecular changes at all three levels. Although a comprehensive picture has not yet been achieved, currently available data can be summarized as follows: (i) there are no changes at the level of transcription of subunit mRNAs studied so far, (ii) evidence is accumulating for a distinct decrease on the protein level in the expression especially of the alpha4-subunit, and (iii) preliminary findings point to a possible correlation of cytoskeletal changes (hyperphosphorylation of tau-protein) with decreased nicotinic acetylcholine receptor expression.

Pages 221-230
James R. Pauly, Ph.D.
Nicotinic cholinergic receptor deficits in Alzheimer's Disease: Where's the smoke?
Summary: Receptor binding studies have uniformly found a significant reduction in the density of neuronal nicotinic cholinergic receptors in postmortem tissue obtained from Alzheimer's Disease (AD) patients. Nicotine is widely recognized as an pharmacological agent that facilitates cognitive performance in human smokers as well as preclinical models utilizing rodents or non-human primates. Furthermore, epidemiological studies have consistently shown that the incidence of neurodegenerative diseases such as AD and Parkinson's Disease is lower in cigarette smokers than age-matched controls. These findings have prompted speculation that brain nicotinic receptors could be important therapeutic targets for Alzheimer's Disease. However, many questions remain with regard to the specificity and significance of the findings that have been reported with brain nicotinic receptors and AD. Few studies have controlled for the potential influence of cigarette smoking, which increases the density of nicotinic receptors in human smokers. Questions also remain concerning alterations in individual nicotinic receptors subtypes as well as the regional variability of the deficits previously reported in AD. Therefore, although the findings related to nicotinic receptors and AD to this date are intriguing, they appear to have raised more questions than they have answered.

Pages 231-247
Dennis T. Villareal and John C. Morris
The Diagnosis of Alzheimer’s Disease
Summary: Dementia constitutes a growing public health crisis. Early and accurate diagnosis of dementia is essential in order to provide patient and family counseling and appropriate treatment, including with specific antidementia drugs as they become increasingly available. Age-related cognitive decline, as compared with dementia, does not seriously interfere with usual activities. The optimal approach to early detection of dementia is clinical examination that incorporates information from a reliable collateral source about how the patient’s cognitive abilities have declined relative to past performance. Alzheimer’s disease (AD), the most common cause of dementia, can be diagnosed clinically with high accuracy (>85%) using standardized criteria. Even incipient AD can be detected with clinical methods alone. Although the typical picture of AD is characterized by gradual onset and progression of memory and other cognitive deficits, in other respects the disease is marked by heterogeneity. Early and late-onset AD represent the most easily recognized subtypes. Research continues towards characterizing a biologic marker but, as of yet, no candidate marker surpasses the high diagnostic accuracy of clinical assessments alone. At present, the diagnosis of AD rests primarily in the hands of the clinician.

Pages 249-263
Dena B. Dubal, Melinda E. Wilson and Phyllis M. Wise
Estradiol: A Protective and Trophic Factor in the Brain
Summary: In recent years our appreciation that estradiol is truly a pleiotropic hormone has grown dramatically. We will review the findings that suggest that estrogens may exert important non-reproductive actions on the brain. These studies provide important insights into the clinical effects of estrogen replacement therapy on age- and disease-related processes in the brain. We will also discuss the multiple cellular and molecular mechanisms that may underlie estradiol’s neurotrophic and neuroprotective effects.

Pages 265-274
David H. Small, Heidi L. Clarris, Timothy G. Williamson, Gullveig Reed, Brian Key, Su San Mok, Konrad Beyreuther, Colin L. Masters, Victor Nurcombe
Neurite-outgrowth regulating functions of the amyloid protein precursor of Alzheimer's disease
Summary: Many studies have shown that breakdown of the amyloid protein precursor (APP) to produce the amyloid protein is an important step in the pathogenic mechanism which causes Alzheimer's disease (AD). However, little is known about the normal function of APP. Developmental studies show that APP expression increases during the period of brain development when neurite outgrowth and synaptogenesis are maximal. APP is expressed highly within growing neurites and in growth cones, and purified APP has been shown to stimulate neurite outgrowth from cells in culture. Thus APP may regulate neurite outgrowth or synaptogenesis in vivo. APP is actively secreted from many cells, and the C-terminally secreted APP has been shown to associate with components of the extracellular matrix, such as the heparan sulphate proteoglycans (HSPGs). Two putative heparin-binding domains on APP have been reported. Binding of HSPGs to an N-terminal heparin-binding domain (HBD-1) stimulates the effect of substrate-bound APP on neurite outgrowth. In the mature nervous system, APP may play an important role in the regulation of wound repair. It is highly likely that studies on the normal functions of APP will shed further light on aspects of the pathogenesis of AD.

Pages 275-285
Tsunao Saitoh and Inhee Mook-Jung
Commentary: Is Understanding the Biological Function of APP Important in Understanding Alzheimer's Disease?
Summary: The presence of mutations around the Abeta sequence in APP provides strong argument for the involvement of APP, and Abeta in particular, in pathogenesis of Alzheimer's disease (AD). In vitro studies demonstrated that Abeta may cause neuronal death, supporting the hypothetical involvement of Abeta in neurodegeneration in AD. However, concentrations of Abeta required for neuronal death are nonphysiologically high. Nevertheless, the predominant idea in the field is that it is sufficient to postulate Abeta as a major culprit in AD development. The question we pose is whether the potentially important involvement of Abeta precludes the etiological (primary) involvement (not pathological, i.e., secondary) of APP functions. We do not have an adequate answer to this question. Current knowledge about APP functions indicates that APP is critically required for the maintenance of neuronal and synaptic structure and function. Because AD is a disease of neuronal and synaptic deterioration, APP may be involved during the course of AD pathogenesis, perhaps secondarily. To ponder the question whether APP may be etiologically involved in AD, much needs to be learned about APP functions. This article is intended to provide a foundation for this challenging task.

Pages 287-295
Richard S. Jope
Cholinergic muscarinic receptor signaling by the phosphoinositide signal transduction system in Alzheimer’s disease
Summary: Recent years have seen the advent of new methods capable of measuring the activity of receptor-coupled, G-protein-mediated, phosphoinositide second messenger production in membranes prepared from postmortem human brain.  Considering the interest in treating Alzheimer’s disease (AD) patients with cholinergic agonists, several investigations have used this new methodology to analyze the functional state of cholinergic muscarinic receptors coupled to phosphoinositide signaling directly in AD brain.  Several, but not all, reports indicate that cholinergic agonist-induced phosphoinositide signaling is severely impaired in AD, potentially due to impaired activation of the receptor-coupled G-protein.  Additionally, deficits in AD also have been reported in the two second messenger pathways activated following phosphoinositide hydrolysis, inositol-1,4,5,-triphosphate receptor binding and protein kinase C activation, indicating further that phosphoinositide signaling is impaired in AD.  Sources of limitations in current methodologies and issues for further exploration are discussed. Speculation concerning potential links between cholinergic receptor-linked signaling and early events in the formation of amyloid plaques and neurofibrillary tangles is provided.  Especially intriguing is the potential for the development of synergistic neurotoxicity where deficits of phosphoinositide signaling and increased production of Aß interact to exacerbate alterations in each process that occur in AD, leading to a feed-forward cycle of progressive neuronal dysfunction.

Pages 297-305
John Q. Trojanowski, Christopher M. Clark, Hiroyuki Arai, and Virginia M.-Y. Lee
Elevated Levels of Tau in Cerebrospinal Fluid: Implications for the Antemortem Diagnosis of Alzheimer's Disease
Summary: Alzheimer's disease (AD) is a heterogeneous group of dementias characterized by progressive cognitive impairments as well as by the accumulation of abundant extracellular deposits of Aß and intra-neuronal neurofibrillary lesions in selectively vulnerable regions of the AD brain. The latter abnormalities (e.g. neurofibrillary tangles, dystrophic neurites, neuropil threads) are aggregates of paired helical filaments (PHFs) formed from altered tau proteins (PHFtau). Although PHFtau and normal central nervous system (CNS) tau are phosphorylated at nearly the same sites, PHFtau is phosphorylated to a greater extent, and alterations in the activity of CNS kinases and phosphatases most likely contribute to the pathogenesis of PHFtau. Since the abundance of neurofibrillary lesions correlates with the dementia in AD, the generation of PHFtau and the formation of neurofibrillary lesions may be part of a cell death pathway leading to massive neuron loss and dementia in AD. Building upon these and other insights into altered tau metabolism in AD, a series of recent studies suggest that the diagnosis of AD may be supported in livingpatients by determining the concentration of tau in cerebrospinal fluid (CSF). We review these promising preliminary studies here, and discuss them in the context of current understanding of the pathobiology of AD.

Pages 307-328
Gail V. W. Johnson and Scott M. Jenkins
Tau Protein in Normal and Alzheimer’s Disease Brain
Summary: In 1975, Weingarten and colleagues isolated a protein factor that was able to induce mi-crotubule formation.  They called this factor tau.  Some ten years later a new era of research on this microtubule-associated protein was launched when several groups almost simultaneously discovered that tau was the predominant protein component of the paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) which are characteristic pathological lesions of the Alzheimer’s disease brain.  Subsequent findings that PHF-tau isolated from Alzheimer’s disease brain was phosphorylated to a greater extent than non-PHF tau, led to extensive investigation into the posttranslational modifications (mainly phosphorylation) of tau in normal and Alzheimer’s disease brain.  The present review highlights the literature concerning the normal functioning and processing of tau protein, and examines the evidence for the involvement of the abnormal posttranslational processing of tau in the pathology of Alzheimer’s disease.  Finally, speculation as to the relationship between abnormal processing of tau, other subcellular abnormalities seen in Alzheimer’s disease, and the pathological causes of the disease are discussed.

Pages 329-351
Gail V. W. Johnson and Judith A. Hartigan
Tau Protein in Normal and Alzheimer’s Disease Brain: An Update
Summary: Tau is a microtubule-associated protein that, in a hyperphosphorylated form, comprises the main component of the paired helical filaments and neurofibrillary tangles found in Alzheimer’s disease (AD) brain.  It is therefore important to understand the normal functioning and processing of tau protein, and the abnormal posttranslational processing of tau in AD pathology.  In 1996, Johnson and Jenkins reviewed the literature on the biochemistry, function, and phosphorylation of tau in normal and AD brain.  Since that time, numerous publications have come out further elucidating the properties of tau.  The present review updates the topics originally covered in the 1996 review, as well as presents a number of new topics.  For example, mutations in the tau gene have been found in several non-AD, autosomal dominant neurodegenerative disorders that exhibit extensive neurofibrillary pathology.  In addition, there is increasing evidence that tau may be involved in signal transduction, organelle transport, and cell growth, independent of its microtubule-binding functions.  Taken together, the research reviewed here demonstrates that tau is a very complex protein with various functions that are intricately regulated.  It is clear that more research is required to completely understand the functions and regulation of tau in normal and AD brain.

 

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