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

Authors: Mukherjee, Atish | Hersh, Louis B.

Article Type: Research Article

Abstract: It is generally accepted that amyloid β peptides (Aβ) play a significant role in the etiology of Alzheimer's disease. The Aβ peptides are produced by the sequential cleavage of an amyloid precursor protein by a βsecretase followed by cleavage by a γ secretase. The clearance of β 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 Aβ 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 Aβ catabolism …and discusses the evidence for their participation in Aβ peptide clearance in vivo. Show more

DOI: 10.3233/JAD-2002-4501

Citation: Journal of Alzheimer's Disease, vol. 4, no. 5, pp. 341-348, 2002

Authors: Small, David H. | Fodero, Lisa R.

Article Type: Research Article

Abstract: There is increasing evidence for disturbances in nicotinic acetylcholine receptor (nAChR) function in Alzheimer's disease (AD). nAChRs are involved in the regulation of many processes, including synaptic plasticity and memory. Levels of nAChRs are altered in the Alzheimer brain and there is evidence that the amyloid βprotein (Aβ) can directly bind to nAChRs. Nicotinic agonists may also protect cells from Aβ toxicity. Drugs which interact with the nAChR or which inhibit Aβ binding to nAChRs may be of value for the treatment of AD.

DOI: 10.3233/JAD-2002-4502

Citation: Journal of Alzheimer's Disease, vol. 4, no. 5, pp. 349-355, 2002

Authors: Korchazhkina, Olga V. | Ashcroft, Alison E. | Kiss, Tamas | Exley, Christopher

Article Type: Research Article

Abstract: The catabolism of amyloid beta peptides (Aβ) may be important in their accumulation in the brain in both early and late-onset Alzheimer's disease (AD). The serine protease plasmin is one of a suite of proteases implicated in AD. It is a promoter of α-cleavage of the amyloid β precursor protein (AβPP) and will degrade Aβ in vitro. Herein we have demonstrated cleavage of the amyloidogenic Aβ25–35 by plasmin to produce the non-amyloidogenic fragment Aβ25–35 . The activity of plasmin was halved by pre-mixing it with aluminium (Al) prior to its addition to the peptide. An interaction between Al and …proteases involved in the catabolism of Aβ might define the putative link between Al and AD. Show more

Keywords: urokinase plasminogen activator system, Plasmin, Amyloid, Aβ catabolism, Aluminium, Alzheimer's disease

DOI: 10.3233/JAD-2002-4503

Citation: Journal of Alzheimer's Disease, vol. 4, no. 5, pp. 357-367, 2002

Authors: Ling, Xie | Martins, R.N. | Racchi, M. | Craft, S. | Helmerhorst, E.

Article Type: Research Article

Abstract: Amyloid β (Aβ) peptides are direct competitive inhibitors of insulin binding and action [25]. We demonstrate that Aβ peptides can inhibit the effect of insulin on the metabolic processing of the amyloid β protein precursor (AβPP). 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 AβPP proteolytic processing. The fact that insulin and Aβ 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 Aβ 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 Aβ blocks the effect of insulin on the release of sAβPPα in chinese hamster ovaries (CHO) cells transfected with insulin receptors. Show more

Keywords: Insulin, Insulin receptor autophosphorylation, amyloid β, amyloid β-protein precursor protein, Alzheimer's disease

DOI: 10.3233/JAD-2002-4504

Citation: Journal of Alzheimer's Disease, vol. 4, no. 5, pp. 369-374, 2002

Authors: Johnson, Gail V.W. | Bailey, Craig D.C.

Article Type: Research Article

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 Aβ 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. Show more

DOI: 10.3233/JAD-2002-4505

Citation: Journal of Alzheimer's Disease, vol. 4, no. 5, pp. 375-398, 2002

Authors: Sánchez, Marina P. | Gonzalo, Isabel | Ávila, Jesús | de Yébenes, Justo García

Article Type: Research Article

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. Show more

DOI: 10.3233/JAD-2002-4506

Citation: Journal of Alzheimer's Disease, vol. 4, no. 5, pp. 399-404, 2002

Authors: Utsuki, Tadanobu | Shoaib, Mohammed | Holloway, Harold W. | Ingram, Donald K. | Wallace, William C. | Haroutunian, Vahram | Sambamurti, Kumar | Lahiri, Debomoy K. | Greig, Nigel H.

Article Type: Research Article

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 β-protein precursor (AβPP) processing in rat. Over-production and/or altered metabolism of AβPP, resulting in increased amyloid β-peptide (Aβ), appear pivotal in the pathogenesis of AD. Aβ is generated proteolytically from βPP by a group of secretases. AβPP cleavage by γ-secretase results in the secretion of a truncated soluble βPP (sAPPγ) that contains intact Aβ. 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 sAPPγ. These actions were blocked by nicotinic receptor antagonism. Whereas nicotinic antagonists alone had no effect on either total sAPP or sAPPγlevels in CSF, muscarinic antagonism significantly elevated them; suggesting that muscarinic rather than nicotinic receptor silence alters processing of AβPP to favor a potentially amyloidogenic route. Combined nicotine and muscarinic antagonism attenuated the action of the latter to elevate sAPPγ, indicating that nicotine modifies AβPP processing away from potentially amyloidogenic products. These results suggest that within the brain, levels of total sAPP, sAPPγ and, accordingly, Aβ are subject to cholinergic manipulation, offering therapeutic potential at the level of AβPP processing to decrease Aβdeposition. Show more

Keywords: Nicotine drug abuse, Alzheimer's dementia, amyloid, β-peptide, cholinergic system, scopolamine, smoking, neuroprotection

DOI: 10.3233/JAD-2002-4507

Citation: Journal of Alzheimer's Disease, vol. 4, no. 5, pp. 405-415, 2002

Authors: Otth, Carola | Concha, Ilona I. | Arendt, Thomas | Stieler, Jens | Schliebs, Reinhard | González-Billault, Christian | Maccioni, Ricardo B.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, neurodegeneration, transgenic mouse Tg2576, amyloid precursor protein, Cdk5, regulatory aspects

DOI: 10.3233/JAD-2002-4508

Citation: Journal of Alzheimer's Disease, vol. 4, no. 5, pp. 417-430, 2002

Authors: Roher, Alex E. | Kokjohn, Tyler A.

Article Type: Research Article

DOI: 10.3233/JAD-2002-4509

Citation: Journal of Alzheimer's Disease, vol. 4, no. 5, pp. 431-434, 2002

Authors: Pasinetti, Giulio Maria

Article Type: Discussion

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, e.g., 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-β (Aβ)1-42 peptide. Recent studies testing non-selective NSAIDs in murine models of AD neuropathology indicated that the frequency of Aβ 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. Show more

DOI: 10.3233/JAD-2002-4510

Citation: Journal of Alzheimer's Disease, vol. 4, no. 5, pp. 435-445, 2002

Article Type: Announcement

DOI: 10.3233/JAD-2002-4511

Citation: Journal of Alzheimer's Disease, vol. 4, no. 5, pp. 447-447, 2002