Showing papers in "Journal of Alzheimer's Disease in 2002"

The significance of environmental factors in the etiology of Alzheimer's disease.

Abstract: The proposition that environmental agents, such as diet, aluminum, and viruses, are as important as genetic factors in the etiology of Alzheimer's disease (AD) was advanced by the authors at the Challenging Views of Alzheimer's Disease meeting held in Cincinnati on July 28 and 29, 2001. Diet, dietary fat, and to a lesser extent, total energy (caloric intake), were found to be significant risk factors for the development of AD in a dozen countries, while fish consumption was found to be a significant risk reduction factor. An acid-forming diet, such as one high in dietary fat or total energy, can lead to increased serum and brain concentrations of aluminum and transition metal ions, which are implicated in oxidative stress potentially leading to the neurological damage characteristic of AD. Many of the risk factors for AD, such as cholesterol and fat, and risk reduction factors, such as whole grain cereals and vegetables, are shared with ischemic heart disease. Aluminum may cause neurological damage and a number of studies have linked aluminum to an increased risk for developing AD. The evidence for viral agents playing a role in AD is the strong association between the presence of HSV1 in brain and carriage of an apoE-epsilon4 allele in the case of AD patients but not of controls; statistical analysis shows the association is causal. Diet, aluminum, and viral infections may increase the prevalence of AD by eliciting inflammation, which may cause the neurological damage that results in AD.

Amyloid β-peptide and amyloid pathology are central to the oxidative stress and inflammatory cascades under which Alzheimer's disease brain exists

Abstract: Alzheimer's disease (AD) brain is characterized by excess deposition of amyloid β-peptide (Aβ), particularly the 42-amino acid peptide (Aβ(1-42)) and by extensive oxidative stress. Several sources of the oxidative stress and inflammatory cascades are likely, including that induced by advanced glycation end products, microglial activation, and by A β(1-42) and its sequelae. This review briefly examines each of these sources of oxidative stress and inflammation in AD brain and discusses their potential roles in the clinical progression of AD dementia.

Non-familial Alzheimer's disease is mainly due to genetic factors.

Abstract: This team takes the position that what is commonly referred to as non-familial Alzheimer's disease (AD) is predominantly due to genetic factors. Population-based studies suggest that genetic factors cause the majority of cases that begin after age 60. There are several lines of evidence supporting this position: Data from the Nun Study suggest that the risk for AD is largely established by early adulthood, implying that later adult exposures likely play only a small role in causation. Family studies show that first-degree blood relatives of persons with non-familial AD have a substantially increased risk of AD relative to controls. Twin studies suggest that the heritability of AD exceeds 60%. Environmental factors, such as socioeconomic status, education, and head injury, are strong risk factors for AD only in individuals with a genetic predisposition. The APOE genotype is a powerful risk factor for AD and accounts for as much as 50%. There are numerous other candidate genes with strong associations with AD that presumably explain the remaining population risk. This paper further reviews the mechanisms associated with AD causation for APOE and other candidate genes and implications for the development of prevention strategies.

Plasma susceptibility to free radical-induced antioxidant consumption and lipid peroxidation is increased in very old subjects with Alzheimer disease

Abstract: Oxidative stress is believed to play a major role in the pathogenesis of Alzheimer disease (AD). Plasma concentrations of vitamins C, A and E, of uric acid, thiols and carotenoids were lower and of malondialdehyde (MDA) higher in 35 AD patients (85.9 +/- 5.5 y) compared to 40 controls 85.5 +/- 4.4 y). Differences were significant for vitamin C, vitamin E, lutein, lycopene, alpha-carotene and MDA (p < 0.001). Plasma exposed to peroxyl radicals showed a rate of antioxidant consumption and of MDA production higher in AD patients than in controls. AD in advanced age is accompanied by a poor plasma antioxidant status and increased plasma lipid peroxidation, as well as by a low resistance to peroxyl radical exposure.

AβPP induces cdk5-dependent tau hyperphosphorylation in transgenic mice Tg2576

Abstract: Previous studies of Aβ-induced neuronal damage of hippocampal cells in culture have provided strong evidence that deregulation of the Cdk5/p35 kinase system is involved in the neurodegeneration pathway. Cdk5 inhibitors and antisense probes neuroprotected hippocampal cells against the neurotoxic action of Aβ. To further investigate the mechanisms underlying the participation of Cdk5 in neuronal degeneration, the transgenic mouse containing the Swedish mutations, Tg2576, was used as an animal model. Immunocytochemical studies using anti-Aβ(1−17) antibody evidenced the presence of labeled small-clustered core plaques in the hippocampus and cortex of 18-month-old transgenic mice brains. The loss of granular cells without a compressed appearance was detected in the vicinity of the cores in the dentate gyrus of the hippocampus. Immunostaining of Tg2576 brain sections with antibodies AT8, PHF1 and GFAP labeled punctuate dystrophic neurites in and around the amyloid core. Reactive astrogliosis around the plaques in the hippocampus was also observed. Studies at the molecular level showed differences in the expression of the truncated Cdk5 activator p25 in the transgenic animal, as compared with wild type controls. However no differences in Cdk5 levels were detected, thus corroborating previous cellular findings. Interestingly, hyperphosphorylated tau epitopes were substantially increased as assessed with the AT8 and PHF1 antibodies, in agreement with the observation of a p25 increase in the transgenic animal. These observations strongly suggest that the increased exposure of Alzheimer's type tau phosphoepitopes in the transgenic mice correlated with deregulation of Cdk5 leading to an increase in p25 levels. These studies also provide further evidence on the links between extraneuronal amyloid deposition and tau pathology.

17α-estradiol and 17β-estradiol treatments are effective in lowering cerebral amyloid-β levels in AβPPSWE transgenic mice

Abstract: Post-menopausal estrogen therapy is associated with a decreased incidence of Alzheimer disease and in vitro models have shown that 17β-estradiol is effective in lowering amyloidogenic processing. To examine the effects of estrogen withdrawal and replacement on amyloid β (Aβ) levels and amyloid β-protein precursor (AβPP) processing in vivo, Swedish mutant AβPP transgenic mice were ovariectomized or sham ovariectomized at four weeks of age and treated with placebo or 17β -o r 17α- estradiol pellets, the latter being a weak estrogen receptor agonist. Compared to sham ovariectomized mice, ovariectomy with placebo did not alter Aβ levels; however, the levels of Aβ were decreased by 27% and 38% in mice treated with 17β- and 17α- estradiol, respectively, with no change in AβPP holoprotein. Endogenous and exogenous estrogen both significantly increased the levels of sAβPPα, the secreted form of AβPP. The ratio of Aβ/sAβPPα, a measure of amyloidogenic processing, was reduced in all estrogen-containing groups. The Aβ lowering effect of 17β- and 17α-estradiol was replicated when estrogens were administered at a more physiological dose in the drinking water, or when mice were ovariectomized at three months of age. The increased efficacy of 17 α-estradiol versus 17β-estradiol may help to develop safe and effective therapeutics. Abbreviations: AβPP - amyloid β-protein precursor, Aβ - amyloid β ,s AβPPα - soluble AβPP cleaved at the α secretase site, AβPPSWE - AβPP Swedish mutant transgenic mice, holoAβ PP -A βPP holoprotein, AD - Alzheimer disease.

Alzheimer's disease: how does it start?

Abstract: Presently, non-genetic Alzheimer's disease (AD) is wrongly classified as a neurodegenerative disorder. When vascular lesions are present, AD is considered to be a vascular dementia. However, compelling evidence indicates that (AD) is a vascular disorder with neurodegenerative consequences. There is an urgent clinical need to ascertain the true cause of this dementia. In this review, evidence indicating that AD is a vascular disorder comes from a number of different disciplines including studies in epidemiology, pharmacology, neuroimaging, clinical medicine, pathology, physiology and experimental research. This collective evidence also addresses many previously puzzling questions regarding: i) past and present treatment failures in AD, ii) strange association of AD risk factors with many vascular-related disorders, iii) parallel lesions, clinical symptoms risk factors and potentially interchangeable treatments present in AD and vascular dementia, iv) historical difficulty in finding neurodegenerative markers to detect AD pre-clinically, and, v) paradoxical pathophysiologic events preceding AD neurodegenerative changes. Re-classifying AD as a vascular disorder would very likely improve the chances of finding a useful treatment for this disorder because clinical study designs could focus on more realistic and relevant pathologic targets than is presently practiced. A short summary of potential new research lines that may provide novel therapy in the treatment and management of AD is discussed.

Cell cycle proteins in Alzheimer's disease: plenty of wheels but no cycle.

Abstract: Increased expression and function of cell cycle proteins in Alzheimer’s disease (AD) brain signifies exit of neurons from the G0 phase of the cell cycle. However we propose that neurons do not actively progress through various stages of the cell cycle and likely do not exit G1. Instead, we believe that multiple intracellular signaling pathways activated during AD induce cell cycle proteins to regulate cell death pathways and contribute to the formation of neurofibrillary tangles.

From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer's disease: The role of NSAIDs and cyclooxygenase in β-amyloidosis and clinical dementia1

Abstract: Epidemiological evidence suggests that non-steroidal anti-inflammatory drugs (NSAID) may protect against Alzheimer's disease (AD) However, therapeutic studies with NSAIDs, including cyclooxygenase (COX) inhibitors and steroids have not supported such epidemiological evidence The apparent inconsistency may be due to the fact that the epidemiological evidence is based on studies examining AD before clinical manifestations are apparent, while therapeutic studies have been carried out on people with illnesses severe enough to exceed the clinical detection threshold Thus, it is conceivable that therapeutic strategies administered during early AD dementia or moderate dementia may not be optimally effective Alternatively, the influence of inflammatory activity in the brain for cases at high risk to develop AD, eg, mild cognitive impairment (MCI) cases, as a potential target of anti-inflammatory drugs in clinical studies maybe more suitable to be studied The primary action of NSAIDs is inhibition of the COX enzymes COX enzymes exist in an inducible form COX-2, that has been found to be elevated in the AD brain, and a constitutive form COX-1 Both COX-1 and COX-2 are known to be involved in numerous inflammatory activities as well as normal neuronal functions In vitro, it has been demonstrated that non-selective inhibitors of COX can preferentially decrease the levels of the highly amyloidogenic amyloid-beta (Abeta)(1-42)peptide Recent studies testing non-selective NSAIDs in murine models of AD neuropathology indicated that the frequency of Abeta plaque deposits in the brains of these animals can be significantly reduced by treatment with the non-selective COX inhibitor ibuprofen These studies and epidemiological data strongly support a therapeutic potential for NSAIDs in the treatment of AD Upon this premise, industry and academia are devoting a tremendous amount of resources to the testing of anti-inflammatory drugs for the treatment of AD However, given the large number of candidate anti-inflammatory drugs and their widely divergent activities, it is essential to optimize drug selection and study design A better understanding of the influence of inflammatory activity in AD, and identification of the specific mechanisms which play an early role in the disease's progression will greatly improve the likelihood of success in efforts to find an effective anti-inflammatory treatment strategy We would like to discuss recent developments reinforcing anti-inflammatory drugs as therapeutic in the treatment of AD amyloidosis, and the relevance of understanding the role of COX and other inflammatory mediators in AD neuropathology and the clinical progression of AD dementia These discussions may provide important criterion for the design of clinical trials of anti-inflammatory drugs in AD

The role of the metabolic lesion in Alzheimer's disease.

Abstract: This paper discusses the hypothesis that the cerebrometabolic deficiency in Alzheimer's disease(AD) is the proximate cause of the clinical disability. Several sets of observations support this hypothesis. (1) Impaired brain metabolism essentially always occurs in clinically significant AD, and the degree of clinical disability is proportional to the degree of metabolic impairment. The earliest, mildest changes in brain metabolism occur even before the onset of measurable cognitive impairment or atrophy. This observation disproves the now outdated assumption that the decreased metabolism is simply a consequence of decreased mental function or of atrophy. One of the important mechanisms reducing brain metabolism in AD appears to be damage to key mitochondrial components. Another appears to relate to inappropriate responses to insulin, i.e. to diabetes of the brain. (2) Inducing impairments of brain metabolism causes changes in mentation that mimic the clinical disabilities in AD, in both humans and experimental animals. (3) Preliminary results from several units suggest that treatment directed at the impairment of brain metabolism can improve neuropsychological functions in AD patients. The hypothesis presented here in no way negates the importance of other mechanisms in AD, such as amyloid accumulation, vascular compromise, and free radical action. However, those other abnormalities including amyloidosis can occur in people whose mentation is still clinically unimpaired. In contrast, once significant decrease in the rate of brain metabolism occurs, mentation becomes defective.

Apolipoprotein E and Alzheimer's disease: The protective effects of ApoE2 and E3

Abstract: G. William Rebecka, Mark Kindyb and Mary Jo LaDuc,∗ Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA Department of Biochemistry, and Stroke Program of Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY 40536, USA Department of Medicine, Division of Geriatrics, Evanston Northwestern Healthcare Research Institute; and Department of Neurobiology and Physiology, and Alzheimer’s Disease Core Center, Northuestern University, Evanston, IL 60201, USA

The glucagon-like peptides: a new genre in therapeutic targets for intervention in Alzheimer's disease.

Abstract: Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an insulinotropic hormone, secreted from the enteroendocrine L cells of the intestinal tract in response to nutrient ingestion. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion, and lowers blood glucose in patients with type 2 diabetes mellitus. GLP-1 receptors, which are coupled to the cyclic AMP second messenger pathway, are expressed throughout the brains of rodents and humans. The chemoarchitecture of receptor distribution in the brain correlates well with a central role for GLP-1 in the regulation of food intake and response to aversive stress. We have recently reported that GLP-1 and several longer acting analogs that bind at the GLP-1 receptor, possess neurotrophic properties, and offer protection against glutamate-induced apoptosis and oxidative injury in cultured neuronal cells. Furthermore, GLP-1 can modify processing of the amyloid beta- protein precursor in cell culture and dose-dependently reduces amyloid beta-peptide levels in the brain in vivo. As such, this review discusses the known role of GLP-1 within the central nervous system, and considers the potential of GLP-1 and analogs as novel therapeutic targets for intervention in Alzheimer's disease (AD) and potentially other central and peripheral neurodegenerative conditions.

The cerebromicrovasculature: A key player in the pathogenesis of Alzheimer's disease

Abstract: Neuronal cell death is the primary underlying pathogenic lesion in Alzheimer's disease (AD). Despite intense research efforts, the mechanisms that contribute to neuronal cell death have not been clarified. In this debate we address the question, Is AD a vascular or metabolic disorder? Here we defend the hypothesis that the cerebromicrovasculature is a key player in the pathogenesis of AD. Evidence is presented that vascular amyloid beta (Abeta) is more closely associated with tau pathology than the distribution of diffuse or neuritic plaque Abeta. Furthermore, brain endothelial cells are identified as important regulators of the neuronal microenvironment, including Abeta levels. Finally, evidence is presented that brain endothelial cells undergo cellular and biochemical changes in AD and that the release of neurotoxic factors from these dysfunctional cells contributes to the neuronal cell loss characteristic of AD.

Tau, where are we now?

Abstract: Tau is a multifunctional protein that was originally identified as a microtubule-associated protein. Tau is primarily a neuronal protein, but it is becoming increasingly evident that tau is present in non-neuronal cells where it also plays important roles. Tau is the primary protein component of the filaments (both paired helical and straight filaments) found in Alzheimer's disease brain. Further there is an ever growing family of neurodegenerative diseases called "tauopathies" where tau pathology is the primary, defining characteristic with little or no Abeta pathology. These findings, along with the fact that mutations in the tau gene cause a group of diseases collectively known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), clearly demonstrate that tau dysfunction results in neuronal dysfunction and death. This review highlights recent findings concerning the normal metabolism and function of tau, as well as the abnormal processing and function of tau in Alzheimer's disease and in the tauopathies, both sporadic and familial.

Thyrotropin releasing hormone (TRH) in the hippocampus of Alzheimer patients.

Abstract: Thyrotropin-releasing hormone (TRH) is best known for its hypothalamic neuroendocrine role in regulating thyroid function. In extra-hypothalamic regions in vitro, we have shown TRH to have a protective effect against synaptic loss and neuronal apoptosis. A role for TRH in Alzheimer's disease (AD) has not been established previously. In this study, we examined the content of the TRH peptide in the hippocampus of elderly controls (n=5) and AD patients (n=7) by radioimmunoassay (RIA). The TRH concentration was decreased in the AD hippocampus compared to normal elderly controls (p < 0.01). In a separate series of experiments utilizing primary cell cultures made from rat hippocampus, TRH peptide concentration was depleted by the addition of TRH antiserum. TRH withdrawal was found to enhance the activity of glycogen synthetase kinase-3 (GSK-3beta), a critical enzyme necessary for the phosphorylation of tau, as well as the phosphorylation of the tau protein itself. This TRH depletion induced upregulation in phosphorylation that was observed to initiate axonal retraction in cultured neurons. These data suggest that TRH within the hippocampus can regulate the activity of various proteins by phosphorylation/dephosphorylation that may be involved in the pathogenesis of AD.

Amyloid beta antagonizes insulin promoted secretion of the amyloid beta protein precursor.

Abstract: Amyloid beta (Abeta) peptides are direct competitive inhibitors of insulin binding and action [25]. We demonstrate that Abeta peptides can inhibit the effect of insulin on the metabolic processing of the amyloid beta protein precursor (AbetaPP). As evidence emerges concerning the role of insulin and insulin like growth factors (IGFs) in learning and memory, recent findings have suggested that insulin may have a significant role in the pathogenetic pathways leading to Alzheimer's disease (AD). As an example several investigators have demonstrated upregulation of insulin receptors and defective insulin receptor signal transduction in AD brains. Moreover insulin has been shown to positively modulate AbetaPP proteolytic processing. The fact that insulin and Abeta appear to share a common system for degradation and disposal as they are both substrates of the insulin degrading enzyme (IDE) suggested the possibility of a reciprocal interference. Here we report that Abeta can directly interfere with insulin receptor signalling inhibiting the autophosphorylation of partially purified insulin receptors. As a consequence of such interaction we also demonstrate that Abeta blocks the effect of insulin on the release of sAbetaPPalpha in chinese hamster ovaries (CHO) cells transfected with insulin receptors.

The nicotinic acetylcholine receptor, smoking, and Alzheimer's disease

Abstract: Cholinergic dysfunction is one of the cornerstones of Alzheimer's disease (AD) pathology. Reviewed here is evidence evaluating relationships between smoking, nicotine exposure, nicotinic cholinergic signaling, and AD. Epidemiological studies initially indicating a lower incidence of AD in smokers now suggest conflicting results. Clinicopathological findings also are mixed as to how smoking behavior affects manifestation of AD markers. Studies that show nicotine-induced increases in nicotinic acetylcholine receptors (nAChR) and protection against age-related nAChR decline contrast, perhaps in a functionally relevant way, to losses of nAChR in AD. Although epidemiological, clinicopathological, and functional studies in humans do not present a cohesive picture, much in vitro data suggests neuroprotective properties of nicotine when used in models of neurodegenerative disorders. Studies of nicotine and nicotinic agonist effects on cognitive function in the non-demented and in AD are not compelling. More work is needed to ascertain whether acute or repetitive activation of nAChR with acute or intermittent exposure to nicotine or the persistent inactivation of nAChR with chronic nicotine exposure is a therapeutic objective and/or explains any pro-cognitive effects of those drugs. Other studies show complex interactions between nAChR, nicotinic agonists, and agents implicated in AD etiology. Thus, while controversies still exist, ongoing research is illuminating how nicotinic receptor changes and functions may be relevant to clinical, pathological and neurochemical changes that occur in AD.

Homocysteine, folate deprivation and Alzheimer neuropathology.

Abstract: Increased levels of homocysteine (HC), arising in some situations via deficiencies in folate--an essential cofactor in metabolic regulation of HC--have long been known to contribute to cardiovascular disorders and stroke. More recently, clinical studies implicate increased HC and reduced folate with neurodegenerative conditions including Alzheimer's disease. It has remained unclear from clinical studies whether the neurotoxicity of increased HC and/or reduced folate is derived from direct detrimental effects on neurons themselves, or is instead derived indirectly following perturbation of nervous system vasculature. However, recent reports from several laboratories provide evidence that HC not only induces direct neurotoxicity, but also potentiates both amyloid-beta and glutamate neurotoxicity. These latter studies leave open the possibility that even mild elevations in HC may place neurons at risk for additional trauma. The potential contribution of folate deficiency and resultant increases in HC to neurodegeneration in AD, and therapeutic approaches to alleviate their impact, is discussed.

Nicotine lowers the secretion of the Alzheimer's amyloid β-protein precursor that contains amyloid β-peptide in rat

Abstract: Reports of an inverse relationship between nicotine intake, due to cigarette smoking, and the incidence of Alzheimer's disease (AD) prompted us to investigate the effects of nicotine on amyloid beta-protein precursor (AbetaPP) processing in rat. Over-production and/or altered metabolism of AbetaPP, resulting in increased amyloid beta-peptide (Abeta), appear pivotal in the pathogenesis of AD. Abeta is generated proteolytically from betaPP by a group of secretases. AbetaPP cleavage by gamma-secretase results in the secretion of a truncated soluble betaPP (sAPPgamma) that contains intact Abeta. Nicotine, 1 and 8 mg/kg/day, doses commensurate with cigarette smoking and a higher but well tolerated dose, respectively, was administered over 14 days and Western blot analysis was performed on sAPP fragments. Both doses significantly reduced sAPPgamma. These actions were blocked by nicotinic receptor antagonism. Whereas nicotinic antagonists alone had no effect on either total sAPP or sAPPgammalevels in CSF, muscarinic antagonism significantly elevated them; suggesting that muscarinic rather than nicotinic receptor silence alters processing of AbetaPP to favor a potentially amyloidogenic route. Combined nicotine and muscarinic antagonism attenuated the action of the latter to elevate sAPPgamma, indicating that nicotine modifies AbetaPP processing away from potentially amyloidogenic products. These results suggest that within the brain, levels of total sAPP, sAPPgamma and, accordingly, Abeta are subject to cholinergic manipulation, offering therapeutic potential at the level of AbetaPP processing to decrease Abetadeposition.

Platelet α- and γ-synucleins in Parkinson's disease and normal control subjects

Abstract: Alpha-synuclein (alphaSN) has been implicated in Parkinson's Disease (PD) and alphaSN is a major component of Lewy bodies (LBs) This study explored platelets as a model system for study of alphaSN metabolism and platelet alphaSN as a diagnostic marker for PD We used Western blot analysis to characterize and compare platelet and brain alpha-, beta- and gammaSN; and to quantitate alphaSN levels in platelets from PD and age-matched controls We found that platelets contain full-length alphaSN and 6 and 12 kDa fragments, and gammaSN-like protein alphaSN and gammaSN were not secreted by thrombin-activated platelets Furthermore, we also found that the alphaSN and gammaSN levels in sporadic PD patients and age-matched normal controls were not significantly different This indicates that platelet alphaSN or gammaSN is not a suitable peripheral diagnostic marker for PD Platelets may be used for study of alphaSN and gammaSN metabolism, and may give some broad insight into the normal functions of alphaSN and gammaSN

Association of novel and established polymorphisms in neuronal nicotinic acetylcholine receptors with sporadic Alzheimer's disease.

Abstract: Since the loss of cholinergic neurons in the Alzheimer's disease (AD) brain was first reported, considerable evidence in vivo and in vitro has accumulated in support of the cholinergic hypothesis of AD. The hypothesis is greatly supported by the fact that the most promising drugs against AD are inhibitors of acetylcholinesterase (AChE). To identify the possible mutations and/or polymorphisms of neuronal nicotinic acetylcholine receptor (nAChR) genes related to the pathogenesis of sporadic AD, we have performed mutational analyses of the major neuronal nAChR genes (CHRNA3, 4, 7 and CHRNB2) expressed in central nervous system. Allelic analysis showed association of specific silent or intronic polymorphisms of the CHRNA3 and CHRNA4 genes and AD. Two novel missense point mutations, Ser413Leu in the CHRNA4 gene and Gln397Pro in the CHRNB2 gene, were identified in two different AD cases but were not found in other AD cases and controls. These findings suggested that genetic polymorphisms of the neuronal nAChR genes might be related to the pathogenesis of sporadic AD.

Regulation of amyloid β-peptide levels by enzymatic degradation

Abstract: It is generally accepted that amyloid beta peptides (Abeta) play a significant role in the etiology of Alzheimer's disease. The Abeta peptides are produced by the sequential cleavage of an amyloid precursor protein by a betasecretase followed by cleavage by a gamma secretase. The clearance of beta appears to be due primarily by the action of one or more peptidases. An imbalance between the rate of synthesis and the rate of clearance of Abeta is now considered a possible contributor to the onset of Alzheimer's disease. This review focuses on peptidases that have been proposed to contribute to Abeta catabolism and discusses the evidence for their participation in Abeta peptide clearance in vivo.

Head trauma and Alzheimer's disease

Abstract: The authors describe a case of a 55 year old woman who was diagnosed with Alzheimer's disease 1.5 years after a car accident in which she experienced a mild concussion. Extensive history taking disclosed no cognitive changes prior to the car accident. The case is discussed in view of the inflammation hypothesis regarding Alzheimer's disease and the role of the apolipoprotein E4 genotype of the patient.

The presence of apoE4, not the absence of apoE3, contributes to AD pathology.

Abstract: ApoE is a component of several classes of lipoproteins regulating lipid metabolism and redistribution [42] and is detected primarily in astrocytes in rodents and in astrocytes and neurons in humans [7,26, 51]. Neuronal apoE levels increase after CNS injuries in humans and rodents [33,38]. The three human isoforms, E2, E3, and E4, (alleles e2, e3, e4) differ by cysteines at two positions (112 and 158) [92]. All other mammalian apoE is E4-like at these cysteine residues, but numerous other differences exist, particularly in the C-terminus, such that rodent apoE cannot be equated with any particular human apoE isoform in its sequence [94]. This is an important consideration when attempting to compare effects of mouse and human apoE in transgenic models. ApoE isoform-specific activities could impact neuronal function through several direct and indirect mechanisms [84], raising the possibility that apoE isoforms differ in the mechanism by which they impact AD pathology [73]. Since the position defended here is that the presence of E4 confers greater risk of AD, an appropriate question is how selection for such a risk factor might occur. The E3 allele has risen to prominence in the last

Progressive supranuclear palsy and tau hyperphosphorylation in a patient with a C212Y parkin mutation

Abstract: Autosomal recessive-juvenile parkinsonism (AR-JP) is one of the most common forms of familial Parkinson's disease (PD) and is related to mutations in the Park-2 gene, encoding for a protein ligase of ubiquitin, parkin. Different mutations located along the parkin gene have been observed in different AR-JP affected families, possibly interfering with the normal function of parkin and the proteasome system. Two cases of patients with AR-JP have been recently described presenting different homo- and heterozygous parkin mutations and limited tau pathology. We report here the case of a patient with clinical and pathological findings compatible with progressive supranuclear palsy (PSP), carrier of a single, heterozygous mutation of the parkin gene, and homozygous for the H1/H1 haplotype in the tau gene. Abnormal tau hyperphosphorylation has been observed in our patient brain samples, suggesting that a partial deficit of parkin, a protein with ubiquitin-ligase function, may trigger tau pathology in individuals with molecular genetic risk factors.

Astrocytosis, microgliosis, metallothionein-I-II and amyloid expression in high cholesterol-fed rabbits.

Abstract: Cholesterol is considered a risk factor in vascular dementia as well as in Alzheimer's disease. Several biochemical, epidemiological and genetic aspects established a correlation between cholesterol concentration and Alzheimer's disease. Microglia activation, astrocytosis with metallothionein-I-II overexpression, amyloid beta intraneuronal accumulation and a rare formation of amyloid beta extracellular positive deposits were the major immunohistochemical features observed in the brain of high cholesterol-fed animals. The relevance on the cholesterol metabolism in Alzheimer's disease pathogenesis is also discussed.

Serum pentosidine as an indicator of Alzheimer's disease

Abstract: Pentosidine, an advanced glycation end product (AGE), was assayed by HPLC in serum proteins from patients with Alzheimer type dementia (AD), patients with diabetes mellitus (D), and healthy (C) age-matched old subjects (mean age from each group = 84 years). Serum pentosidine was significantly different between the three groups despite similar renal function (serum creatinine < 160 micromol/L). In all groups of patients, pentosidine was independent of glycated hemoglobin (HbA1C) and the early glycation marker fructosamine and appeared to be an independent marker, mainly bound to serum albumin. Pentosidine could be an important factor useful for the diagnosis of Alzheimer's disease.