Journal of Alzheimer's Disease - Volume 9, issue s3

Authors: Nixon, Ralph A. | Cataldo, Anne M.

Article Type: Research Article

Abstract: The identification of cathepsins in amyloid-β plaques revealed broad dysfunction of the lysosomal system in Alzheimer's disease (AD). Coinciding with the discovery that proteolysis is required to generate the Aβ-peptide, these findings heralded an era of intense investigation on proteases in neurodegeneration. This review traces lysosomal system pathology from its early characterization to its origins within two pathways leading to the lysosome, the endocytic and autophagic pathways. An understanding has grown about how these two pathways are adversely influenced by normal brain aging and by genetic and environmental risk factors for AD, resulting in increased susceptibility of neurons to injury, …amyloidogenesis, and neurodegeneration. Show more

Keywords: Amyloid-β, cathepsin, apoptosis, endosome, autophagy, necrosis, Alzheimer's disease, protease, endocytosis

DOI: 10.3233/JAD-2006-9S331

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 277-289, 2006

Authors: Perl, Daniel P. | Moalem, Sharon

Article Type: Research Article

Abstract: It is now 25 years since the publication of our original paper investigating the association aluminum with Alzheimer's disease. This publication reported on the results of scanning electron microscopy coupled with x-ray spectrometry microprobe elemental studies of both neurofibrillary tangle-bearing and tangle-free neurons in the hippocampus of cases of Alzheimer's disease and controls. Peaks related to the presence of aluminum were consistently detected within the tangle-bearing neurons. This paper supported the association of aluminum and Alzheimer's disease on the cellular level of resolution and caused considerable interest and discussion. Subsequent work demonstrated prominent evidence of aluminum accumulation in the tangle-bearing …neurons of cases of amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. This latter observation has now been replicated using five different forms of microanalysis. Finally, using laser microprobe mass analysis, we demonstrated that the abnormally high aluminum-related signal which we originally detected was actually located within the neurofibrillary tangle, itself, and was accompanied by excess concentrations of iron. Although it is unlikely that aluminum represents an etiologic cause of Alzheimer's disease, we believe that this highly reactive element, known to cross-link hyperphosphorylated proteins, may play an active role in the pathogenesis of critical neuropathologic lesions in Alzheimer's disease and other related disorders. Show more

DOI: 10.3233/JAD-2006-9S332

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 291-300, 2006

Authors: Perry, George

Article Type: Research Article

Abstract: Dissection of neurofibrillary tangles has been confounded by the insolubility of their fibers. While the majority of biochemical studies have considered τ filaments equivalent to neurofibrillary tangles, they forget that the former are soluble and the latter completely resistant to solvents. What, then, accounts for the insolubility of neurofibrillary tangles while τ filaments are soluble? Investigation of these distinctions played a critical role in our findings on proteolytic abnormalities and oxidative stress.

DOI: 10.3233/JAD-2006-9S333

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 301-304, 2006

Authors: Smith, Mark A.

Article Type: Research Article

Abstract: The role of oxidative stress in the pathogenesis of Alzheimer disease has gone from epiphenomena to phenomena. This transition, from disregarded to accepted theory, started in the early-mid 1990s and was accelerated by a number of reports in the literature showing that redox-active sources of transition metals, such as iron, were increased in the brain at early stages of disease. As such, it became apparent that not only was there damage but, more importantly, the machinery to exact such damage was ever present. In this review, the author chronicles his personal perspective on the past, present, and future of oxidative …stress in Alzheimer disease. Show more

DOI: 10.3233/JAD-2006-9S334

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 305-308, 2006

Authors: Takashima, Akihiko

Article Type: Research Article

Abstract: Glycogen synthase kinase-3 (GSK-3) is a pivotal molecule in the development of Alzheimer's disease (AD). GSK-3β is involved in the formation of paired helical filament (PHF)-tau, which is an integral component of the neurofibrillary tangle (NFT) deposits that disrupt neuronal function, and a marker of neurodegeneration in AD. GSK-3β has exactly the same oligonucleotide sequence as tau-protein kinase I (TPKI), which was first purified from the microtubule fraction of bovine brain. Initially, we discovered that GSK-3β was involved in amyloid-β (Aβ)-induced neuronal death in rat hippocampal cultures. In the present review, we discuss our initial in vitro results and additional …investigations showing that Aβ activates GSK-3β through impairment of phosphatidylinositol-3 (PI3)/Akt signaling; that Aβ-activated GSK-3β induces hyperphosphorylation of tau, NFT formation, neuronal death, and synaptic loss (all found in the AD brain); that GSK-3β can induce memory deficits in vivo; and that inhibition of GSK-3α (an isoform of GSK-3β) reduces Aβ production. These combined results strongly suggest that GSK-3 activation is a critical step in brain aging and the cascade of detrimental events in AD, preceding both the NFT and neuronal death pathways. Therefore, therapeutics targeted to inhibiting GSK-3 may be beneficial in the treatment of this devastating disease. Show more

Keywords: GSK-3β, NFT, Aβ, AD, tauopathy

DOI: 10.3233/JAD-2006-9S335

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 309-317, 2006

Authors: van Leeuwen, F.W. | Hol, E.M. | Fischer, D.F.

Article Type: Research Article

Abstract: Neuronal homeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the ubiquitin-proteasome system (UPS) and discovered a frameshift protein for ubiquitin (UBB+1 ), that accumulates in the neuritic plaques and tangles in patients with Alzheimer's disease (AD). UBB+1 , unable to tag proteins to be degraded, has been shown to be a substrate for ubiquitination and subsequent proteasomal degradation. If UBB+1 is accumulated, it inhibits the proteasome, which may result in neuronal death. We showed that UBB+1 …is also present in other tauopathies (e.g. Pick's disease) and in several polyglutamine diseases, but remarkably not in synucleinopathies (e.g. Parkinson's disease). Accumulation of UBB+1 -being a reporter for proteasomal dysfunctioning- thus differentiates between these conformational diseases. The accumulation of UBB+1 causes a dysfunctional UPS in these multifactorial neurodegenerative diseases. Novel transgenic mouse models and large-scale expression profiling and functional analyses of enzymes of the UPS compounds – enabling us to identify the targets of the UPS in these conformational diseases – may now pave the way for intervention and treatment of AD. Show more

Keywords: Conformational diseases, molecular misreading, polyglutamine diseases, synucleinopathies, tauopathies, vasopressin

DOI: 10.3233/JAD-2006-9S336

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 319-325, 2006

Authors: Levy, Efrat | Prelli, Frances | Frangione, Blas

Article Type: Research Article

Abstract: Amyloid protein deposited in cerebral vessel walls and diffuse plaques of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), is similar to the 40–42 residues amyloid β (Aβ) in vessel walls and senile plaques in brains of patients with Alzheimer's disease (AD), Down's syndrome, and familial and sporadic cerebral amyloid angiopathy (CAA). In 1990 we sequenced the amyloid β-protein precursor (AβPP) gene from HCHWA-D patients revealing a single mutation that results in an amino acid substitution, Aβ E22Q. Subsequent identification of additional mutations in the AβPP gene in familial AD (FAD) pedigrees revealed that whereas substitutions in the …middle of Aβ, residues Aβ21-23, are predominantly vasculotropic, those found amino- or carboxyl-terminal to the Aβ sequence within AβPP enhance amyloid parenchymal plaque deposition. Studies of transfected cells showed that substitutions amino- or carboxyl-terminal to Aβ lead to either greater Aβ production or to enhanced secretion of the more hydrophobic thus more fibrillogenic Aβ1-42. Substitutions in the center of Aβ facilitate rapid aggregation and fibrillization, slower clearance across the blood-brain barrier and perivascular drainage to the systemic circulation, possibly higher resistance to proteolysis, and enhanced toxicity towards endothelial and smooth muscle cells. However, most AD patients have no genetic defects in AβPP, indicating that other factors may alter Aβ production, conformation, and/or clearance initiating the disease process. Show more

Keywords: Alzheimer's disease, hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), cerebral amyloid angiopathy (CAA), amyloid β-protein precursor (AβPP), amyloid β (Aβ)

DOI: 10.3233/JAD-2006-9S337

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 329-339, 2006

Authors: Goate, Alison

Article Type: Research Article

Abstract: In 1991 we described a missense mutation in the amyloid β-protein precursor (AβPP) gene in two familial Alzheimer's disease (FAD) kindreds. This gene encodes the amyloid β peptide deposited in senile plaques in AD. We made four predictions based upon these results: 1. Other FAD kindreds would be identified wth AβPP mutations; 2. FAD is genetically heterogeneous; 3. Aβ deposition is central to the pathogenesis of AD and 4, Regulatory variants in the AβPP gene lead to late onset AD. In the ensuing years substantial evidence has accrued in support of these predictions. Nineteen mutations in the AβPP gene have …been reported. These mutations have all been shown to alter AβPP processing or Aβ fibrillogenesis, leading to early Aβ deposition. Furthermore, mutations in the genes encoding presenilin 1 and presenilin 2, that cause FAD, also lead to changes in AβPP processing and Aβ deposition. Together these observations strongly support the hypothesis that Aβ deposition is central to AD pathogenesis. Suprisingly, the fourth prediction, that variation in AβPP expression may predispose to late onset AD, has not been rigorously tested, despite the fact that overexpression of AβPP is sufficient to cause dementia and AD neuropathology in Down Syndrome. Show more

Keywords: Familial Alzheimer's disease, Amyloid β-protein precursor, Amyloid β, gene, mutation, pathogenesis

DOI: 10.3233/JAD-2006-9S338

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 341-347, 2006

Authors: Goldgaber, Dmitry

Article Type: Research Article

Abstract: When I decided to clone the amyloid gene I did not know that there were some twenty groups around the research world that desperately tried to do the same. If I knew that I would have never started the project. I was so ignorant about the disease that I did not know how to spell the name Alzheimer. I had to look at the papers of other researchers to make sure that my spelling was correct. After the cloning, I was invited to numerous national and international meetings on AD. These meetings became my University where I majored in AD.

DOI: 10.3233/JAD-2006-9S339

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 349-360, 2006

Authors: Roses, Allen D.

Article Type: Research Article

Abstract: The association of Apolipoprotein E-4 with the age of onset of common late-onset Alzheimer's disease (AD) was originally reported in three 1993 papers from the Duke ADRC (Alzheimer's Disease Research Center) group [1--3]. The Center was investigating two diverse experimental streams that led to this discovery. The first being a genetic linkage study performed in multiplex familial late-onset AD in which a linkage was discovered at chromosome 19q13 [4,5]. The 1991 multilocus analysis of linkage had been considered very controversial [6]. The second stream came from a series of amyloid-β binding studies in which a consistent protein “impurity” was present …on gel separation analyses [1]. After sequencing this “impurity” band, several tryptic peptide sequences were found to be identical for apoE which, at that time, had no known association with Alzheimer's disease. The flash of recognition was the knowledge that APOE was one of the first genes localized to chromosome 19 in the mid-1980's. Within a three week period in late 1992, a highly significant association was identified in clinical patients from multiplex families, in sporadic clinical patients, and in autopsy diagnosed series [1,2]. Within the first two months of 1993, it was possible to clearly demonstrate that the APOE isoforms were associated with differing ages of onset, but the course of illness following diagnosis was related more to age than APOE genotype [3]. The earliest submitted paper reported the familial association and amyloid-β binding [1]. The second reported the association with common sporadic late-onset, [not-known to be familial] AD patients [2]. The third reported that APOE4 carriers had earlier rates of onset of clinical disease than APOE2 or APOE3 carriers [3]. Subsequently, over more than a decade, the biological expression of apoE in human neurons was confirmed as distinct from rodent brain [7,8] Proteomic experiments and positron emission tomography data have led to a series of clinical trials with agents selected to increase glucose utilization. These agents also regulate inflammatory responses of neural cells. Rosiglitazone, a PPARγ agonist which also leads to mitochondrial proliferation shown efficacy as a monotherapy in a Phase IIB clinical trial of 511 patients in an APOE allele-specific analysis. Show more

DOI: 10.3233/JAD-2006-9S340

Citation: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 361-366, 2006