Journal of Alzheimer's Disease - Volume 1, issue 4-5

Authors: Grant, William B.

Article Type: Research Article

Abstract: With the republication of Grant (18), 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 contri-butes 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. Show more

DOI: 10.3233/JAD-1999-14-501

Citation: Journal of Alzheimer's Disease, vol. 1, no. 4-5, pp. 197-201, 1999

Authors: Smith, Mark A. | Petot, Grace J. | Perry, George

Article Type: Research Article

DOI: 10.3233/JAD-1999-14-502

Citation: Journal of Alzheimer's Disease, vol. 1, no. 4-5, pp. 203-206, 1999

Authors: Wevers, Andrea | Schröder, Hannsjörg

Article Type: Research Article

Abstract: Nicotinic cholinoceptive dysfunction associated with cognitive impairment is a leading neurochemical feature of Alzheimer's disease. There-fore, 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 com-prehensive 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 α4-subunit, and (iii) preliminary findings point to a possible correlation of cytoskeletal changes (hyperphosphorylation of ô-protein) with decreased nicotinic acetylcholine receptor expression. Show more

DOI: 10.3233/JAD-1999-14-503

Citation: Journal of Alzheimer's Disease, vol. 1, no. 4-5, pp. 207-219, 1999

Authors: Pauly, James R.

Article Type: Research Article

Abstract: Receptor binding studies have uniform-ly found a significant reduction in the density of neuronal nicotinic cholinergic receptors in postmortem tissue obtained from Alzheimer's Disease (AD) pa-tients. Nicotine is widely recognized as an pharma-cological 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. Show more

DOI: 10.3233/JAD-1999-14-504

Citation: Journal of Alzheimer's Disease, vol. 1, no. 4-5, pp. 221-230, 1999

Authors: Jope, Richard S.

Article Type: Research Article

Abstract: Recent years have seen the advent of new methods capable of measuring the activity of receptor-coupled, G-protein-mediated, phosphoino-sitide second messenger production in membranes prepared from postmortem human brain. Considering the interest in treating Alzheimer's disease (AD) patients with cholinergic agonists, several investiga-tions 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. Ad-ditionally, deficits in AD also have been reported in the two …second messenger pathways activated following phosphoinositide hydrolysis, inositol-1,4,5,-triphos-phate 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 intri-guing is the potential for the development of synergistic neurotoxicity where deficits of phosphoinositide signaling and increased production of Aβ interact to exacerbate alterations in each process that occur in AD, leading to a feed-forward cycle of progressive neuronal dysfunction. Show more

Keywords: acetylcholine, β-amyloid, G-protein, postmortem, protein kinase

DOI: 10.3233/JAD-1999-14-505

Citation: Journal of Alzheimer's Disease, vol. 1, no. 4-5, pp. 231-247, 1999

Authors: Villareal, Dennis T. | Morris, John C.

Article Type: Research Article

Abstract: 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. Show more

Keywords: Age-related cognitive decline, dementia, memory loss

DOI: 10.3233/JAD-1999-14-506

Citation: Journal of Alzheimer's Disease, vol. 1, no. 4-5, pp. 249-263, 1999

Authors: Dubal, Dena B. | Wilson, Melinda E. | Wise, Phyllis M.

Article Type: Research Article

Abstract: In recent years our appreciation that estradiol is truly a pleiotropic hormone has grown dramatically. We will review the findings that suggest that estrogens1 1 Estrogens are synthesized by the ovary and several other tissues. They contain 18 carbon atoms and an aromatized A ring. Estradiol is the predominant and most potent of the endogenously synthesized estrogens in adult premenopausal women. Preparations used in estrogen replacement therapy contain a variety of estrogenic compounds. Studies performed using laboratory animals have used a variety of estrogens to replace the endogenous steroid, including estradiol. 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. Estrogens are synthesized by the ovary and several other tissues. They contain 18 carbon atoms and an aromatized A ring. Estradiol is the predominant and most potent of the endogenously synthesized estrogens in adult premenopausal women. Preparations used in estrogen replacement therapy contain a variety of estrogenic compounds. Studies performed using laboratory animals have used a variety of estrogens to replace the endogenous steroid, including estradiol. Show more

DOI: 10.3233/JAD-1999-14-507

Citation: Journal of Alzheimer's Disease, vol. 1, no. 4-5, pp. 265-274, 1999

Authors: Small, D.H. | Clarris, H.L. | Williamson, T.G. | Reed, G. | Key, B. | Mok, S.S. | Beyreuther, K. | Masters, C.L. | Nurcombe, V.

Article Type: Research Article

Abstract: 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 is 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. Show more

Keywords: trophic proteoglycan , embryogenesis, dementia, heparin

DOI: 10.3233/JAD-1999-14-508

Citation: Journal of Alzheimer's Disease, vol. 1, no. 4-5, pp. 275-285, 1999

Authors: Saitoh, Tsunao | Mook-Jung, Inhee

Article Type: Research Article

Abstract: The presence of mutations around the Aβ sequence in APP provides strong argument for the involvement of APP, and Aβ in particular, in pathogenesis of Alzheimer's disease (AD). In vitro studies demonstrated that Aβ may cause neuronal death, supporting the hypothetical involvement of Aβ in neurodegeneration in AD. However, concentrations of Aβ required for neuronal death are nonphysio-logically high. Nevertheless, the predominant idea in the field is that it is sufficient to postulate Aβ as a major culprit in AD development. The question we pose is whether the potentially important involvement of Aβ 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. Show more

DOI: 10.3233/JAD-1999-14-509

Citation: Journal of Alzheimer's Disease, vol. 1, no. 4-5, pp. 287-295, 1999

Authors: Trojanowski, John Q. | Clark, Christopher M. | Arai, Hiroyuki | Lee, Virginia M.-Y.

Article Type: Research Article

Abstract: 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 studies suggest that the diagnosis of AD may be supported in living patients by determining the concentration of tau in cerebrospinal fluid (CSF). We review these promising studies here, and discuss them in the context of current understanding of the pathobiology of AD. Show more

Keywords: PHFs, PHFtau, neurofibrillary tangles, dementia

DOI: 10.3233/JAD-1999-14-510

Citation: Journal of Alzheimer's Disease, vol. 1, no. 4-5, pp. 297-305, 1999

Authors: Johnson, Gail V.W. | Jenkins, Scott M.

Article Type: Research Article

Abstract: In 1975, Weingarten and colleagues isolated a protein factor that was able to induce microtubule formation. They called this factor tau (t). 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. Show more

Keywords: kinases, oxidative stress, pathology, phosphatases, phosphorylation

DOI: 10.3233/JAD-1999-14-511

Citation: Journal of Alzheimer's Disease, vol. 1, no. 4-5, pp. 307-328, 1999

Authors: Johnson, Gail V.W. | Hartigan, Judith A.

Article Type: Research Article

Abstract: 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. Show more

Keywords: microtubule, phosphorylation, PHF, kinase, phosphatase

DOI: 10.3233/JAD-1999-14-512

Citation: Journal of Alzheimer's Disease, vol. 1, no. 4-5, pp. 329-351, 1999