Alzheimer Disease: Duff K

Paulsen JS, Duff K. · University of Iowa, Psychiatry Research, 1-305 Medical Education Building, Iowa City, IA 52242-1000, USA. · Neurology. · Pubmed #19332688 No free full text.

This publication has no abstract.

Small SA, Duff K. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. · Neuron. · Pubmed #19038212 No free full text.

Abstract: Alzheimer's disease is characterized by abnormal elevation of Abeta peptide and abnormal hyperphosphorylation of the tau protein. The "amyloid hypothesis," which is based on molecular defects observed in autosomal-dominant early-onset Alzheimer's disease (EOAD), suggests a serial model of causality, whereby elevation of Abeta drives other disease features including tau hyperphosphorylation. Here, we review recent evidence from drug trials, genetic studies, and experimental work in animal models that suggests that an alternative model might exist in late-onset AD (LOAD), the complex and more common form of the disease. Specifically, we hypothesize a "dual pathway" model of causality, whereby Abeta and tau can be linked by separate mechanisms driven by a common upstream driver. This model may account for the results of recent drug trials and, if confirmed, may guide future drug development.

Duff K. · Taub Institute, Columbia University, New York State Psychiatric Institute, 650 W168th St, New York, NY 10032, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17132962 No free full text.

This publication has no abstract.

Duff K, Suleman F. · Nathan Kline Institute, Department of Psychiatry, New York University, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. · Brief Funct Genomic Proteomic. · Pubmed #15163359 links to  free full text

Abstract: Transgenic mice have been created in an attempt to generate models of human Alzheimer's disease, but success has been partial and unpredictable. The overall aim of this paper is to illustrate how genomics can be used in translational research, turning genetic information in the form of pathogenic mutations into clinically useful drugs against a major human disease. This paper will illustrate how genetic information allows researchers to dissect the aetiology of a disease and then replicate the disease in vivo through the process of transgenesis. The limitations of recreating a condition like Alzheimer's disease in a transgenic mouse, how far the mice have advanced understanding of the disease and how useful they have been for the development of therapeutics will then be discussed.

Burns M, Duff K. · Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York 10962, USA. · Neurochem Res. · Pubmed #12737522 No free full text.

Abstract: Cholesterol has been implicated in the pathogenesis of Alzheimer's disease, both through intracellular effects, and through an extracellular effect due to its physical interaction with plaque associated amyloid. Epidemiology studies have implicated high cholesterol as a risk factor for AD, and have shown that the use of cholesterol reducing agents (statins) can be protective against the disease. We, and others have shown that cholesterol levels modulate the processing of the amyloid precursor protein (APP) both in vivo and in vitro, affecting the accumulation of Abeta (Abeta) peptides which may directly impact the risk of AD. This review describes the biology of sterols, and identifies how cholesterol may exacerbate the pathogenesis of AD. Data from in vivo and in vitro studies will then be presented to describe how treatments aimed at modulating lipid levels may be efficacious in treating AD.

Burns M, Duff K. · Center for Dementia Research, Nathan S. Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. · Ann N Y Acad Sci. · Pubmed #12480774 No free full text.

Abstract: Cholesterol has been implicated in the pathogenesis of amyloid plaques in Alzheimer's disease (AD) and in the formation of neurofibrillary pathology in Niemann-Pick disease. Several epidemiology studies have implicated high cholesterol as a risk factor for AD and have shown that the use of cholesterol-reducing agents (statins) can be protective against the disease. We and others have shown that cholesterol levels modulate the processing of the amyloid precursor protein (APP) both in vivo and in vitro, affecting the accumulation of A-beta (Abeta) peptides that may directly impact the risk of AD. Mutations in the Niemann-Pick C gene (NPC) result in deficient cholesterol transport/storage. Clinically, Niemann-Pick disease causes a severe childhood lipidosis, with neurodegeneration characterized by the presence of AD-type neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Studies of mouse models of NPC show that defects in cellular cholesterol trafficking are associated with enhanced generation of Abeta and the hyperphosphorylation of tau, further implicating the cholesterol homeostasis pathway as a risk factor for amyloidosis.

Duff K. · Nathan Kline Institute, 140 Old Orangeburg Rd, Orangeburg, NY 10962, USA. · Biochem Soc Symp. · Pubmed #11447835 No free full text.

Abstract: A range of transgenic mice have been created to model Alzheimer's disease. These include mice expressing human forms of the amyloid precursor protein, the presenilins and, more recently, tau. Several of the models develop features of the disease including amyloid pathology, cholinergic deficits, neurodegeneration and cognitive impairment. Progress in the characterization and use of these model animals is discussed.

Gandy S, Duff K. · Department of Psychiatry, The Nathan S. Kline Institute for Psychiatric Research, New York University, Orangeburg, NY 10962, USA. · Exp Gerontol. · Pubmed #10959038 No free full text.

Abstract: Estrogen deprivation has been implicated as a risk factor in Alzheimer's disease (AD) as epidemiological data suggests that estrogen replacement therapy can protect against the onset, and progression of the disease. Biochemical data suggests that estrogen exerts its affect through the processing of the amyloid precursor protein to beta-amyloid which is deposited in the brains of patients with AD. The effects of estrogens may be more widespread, however, as it has been implicated in the maintenance of neuronal architecture and protection from free radicals. This review aims to discuss the various roles of estrogen in the development of AD.

Duff K. · Nathan Kline Institute, Orangeburg, NY 10962, USA. · Trends Neurosci. · Pubmed #10529812 No free full text.

This publication has no abstract.

Kwan AC, Duff K, Gouras GK, Webb WW. · School of Applied and Engineering Physics, Cornell University, Ithaca, New York 14853, USA. · Opt Express. · Pubmed #19259208 No free full text.

Abstract: Intrinsic optical emissions, such as autofluorescence and second harmonic generation (SHG), are potentially useful for functional fluorescence imaging and biomedical disease diagnosis for neurodegenerative diseases such as Alzheimer's disease (AD). Here, using multiphoton and SHG microscopy, we identified sources of intrinsic emissions in ex vivo, acute brain slices from AD transgenic mouse models. We observed autofluorescence and SHG at senile plaques as well as characterized their emission spectra. The utility of intrinsic emissions was demonstrated by imaging senile plaque autofluorescence in conjunction with SHG from microtubule arrays to assess the polarity of microtubules near pathological lesions. Our results suggest that tissues from AD transgenic models contain distinct intrinsic emissions, which can provide valuable information about the disease mechanisms.

Schultz SK, Magnotta V, Duff K, Boles Ponto LL, Moser DJ. · University of Iowa Department of Psychiatry, Carver College of Medicine, Iowa City, IA 52242-1000, USA. · Ann Clin Psychiatry. · Pubmed #19034752 No free full text.

Abstract: BACKGROUND: This study evaluated brain volumes in healthy older subjects without dementia who presented with memory complaints. The objective was to examine cortical volumes in relation to cognitive performance among patients who do not have dementia, but who do have mild cognitive deficits. METHODS: Fifteen participants were evaluated (mean age = 71.8 +/- 6.2). Brain structure was measured via high-resolution magnetic resonance imaging to quantify gray and white matter volumes. Volumetric measures were assessed relative to cognitive function in separate regression models controlling for total cerebral volume. Reported here are measures of global cognitive performance using the Mattis Dementia Rating Scale (DRS) in relation to volumetric measures. RESULTS: Baseline MMSE scores ranged from 27 to 30 (mean = 29.3; SD = 0.9). After controlling for total cerebral volume, we observed that lower white matter volume in the temporal lobe [F(1,14) = 5.72, p = 0.03] was associated with lower performance on the Mattis Dementia Rating Scale (DRS). CONCLUSIONS: Structural imaging may help provide useful clinical information in the context of mild cognitive decline. Currently, the diagnosis of dementia relies on longitudinal measures of cognition. Future studies will help determine whether the addition of brain imaging may enhance diagnostic certainty as well as predict long-term outcome.

Duff K, Humphreys Clark JD, O'Bryant SE, Mold JW, Schiffer RB, Sutker PB. · Roy J. and Lucille A. Carver College of Medicine, Department of Psychiatry, University of Iowa, 1-308 MEB, Iowa City, IA 52242-1000, USA. · Arch Clin Neuropsychol. · Pubmed #18639437 No free full text.

Abstract: Although initially developed as a brief dementia battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has not yet demonstrated its sensitivity, specificity, and positive and negative predictive powers in detecting cognitive impairment in patients with Alzheimer's disease (AD). Therefore, the current study examined the clinical utility of the RBANS by comparing two age-, education-, and gender-matched groups: patients with AD (n=69) and comparators (n=69). Significant differences (p<0.001) were observed on the RBANS Total score, all 5 Indexes, and all 12 subtests, with patients performing worse than the comparison participants. An optimal balance between sensitivity and specificity on RBANS scores was obtained when cutoffs of one and one and a half standard deviations below the mean of the comparison sample were implemented. Areas under the Receiver Operating Characteristic curves for all RBANS Indexes were impressive though Immediate and Delayed Memory Indexes were excellent (0.96 and 0.98, respectively). Results suggest that RBANS scores yield excellent estimates of diagnostic accuracy and that the RBANS is a useful screening tool in detection of cognitive deficits associated with AD.

Liu L, Orozco IJ, Planel E, Wen Y, Bretteville A, Krishnamurthy P, Wang L, Herman M, Figueroa H, Yu WH, Arancio O, Duff K. · Department of Pathology, Taub Institute for Research on Alzheimer's Disease, Columbia University, Black Building #5-513, 650 West 168th Street, New York, NY 10032, USA. · Neurobiol Dis. · Pubmed #18504134 No free full text.

Abstract: In the last decade, multiple lines of transgenic APP overexpressing mice have been created that recapitulate certain aspects of Alzheimer's disease (AD). However, none of the previously reported transgenic APP overexpressing rat models developed AD-like beta-amyloid (Abeta) deposits, or age-related learning and memory deficits. In the present study, we have characterized a transgenic rat model overexpressing transgenes with three, familial AD mutations (two in APP and one in PS1) that were developed by Flood et al. [Flood, D.G., et al., Abeta deposition in a transgenic rat model of Alzheimer's disease. Society for Neuroscience 2003, Washington, DC, 2003]. From the age of 9 months, these rats develop Abeta deposits in both diffuse and compact forms, with the latter being closely associated with activated microglia and reactive astrocytes. Impaired long-term potentiation (LTP) was revealed by electrophysiological recordings performed on hippocampal slices from rats at 7 months of age, which is 2 months before the appearance of amyloid plaques. The deficit in LTP was accompanied by impaired spatial learning and memory in the Morris water maze, which became more pronounced in transgenic rats of 13 months of age. For Tg rats of both ages, there was a trend for cognitive impairment to correlate with total Abeta42 levels in the hippocampus. The rat model therefore recapitulates AD-like amyloid pathology and cognitive impairment. The advantage of the rat model over the available mouse models is that rats provide better opportunities for advanced studies, such as serial CSF sampling, electrophysiology, neuroimaging, cell-based transplant manipulations, and complex behavioral testing.

Muhammad A, Flores I, Zhang H, Yu R, Staniszewski A, Planel E, Herman M, Ho L, Kreber R, Honig LS, Ganetzky B, Duff K, Arancio O, Small SA. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. · Proc Natl Acad Sci U S A. · Pubmed #18480253 links to  free full text

Abstract: Although deficiencies in the retromer sorting pathway have been linked to late-onset Alzheimer's disease, whether these deficiencies underlie the disease remains unknown. Here we characterized two genetically modified animal models to test separate but related questions about the effects that retromer deficiency has on the brain. First, testing for cognitive defects, we investigated retromer-deficient mice and found that they develop hippocampal-dependent memory and synaptic dysfunction, which was associated with elevations in endogenous Abeta peptide. Second, testing for neurodegeneration and amyloid deposits, we investigated retromer-deficient flies expressing human wild-type amyloid precursor protein (APP) and human beta-site APP-cleaving enzyme (BACE) and found that they develop neuronal loss and human Abeta aggregates. By recapitulating features of the disease, these animal models suggest that retromer deficiency observed in late-onset Alzheimer's disease can contribute to disease pathogenesis.

Duff K, Beglinger LJ, Van Der Heiden S, Moser DJ, Arndt S, Schultz SK, Paulsen JS. · Department of Psychiatry, College of Medicine, University of Iowa, Iowa City, IA 52242-1000, USA. · Int Psychogeriatr. · Pubmed #18405398 No free full text.

Abstract: BACKGROUND: Practice effects have been widely reported in healthy older adults, but these improvements due to repeat exposure to test materials have been more equivocal in individuals with mild cognitive impairment (MCI). METHODS: The current study examined short-term practice effects in MCI by repeating a brief battery of cognitive tests across one week in 59 older adults with amnestic MCI and 62 intact older adults. RESULTS: Participants with amnestic MCI showed significantly greater improvements on two delayed recall measures (p < 0.01) compared to intact peers. All other practice effects were comparable between these two groups. Practice effects significantly improved scores in the MCI group so that 49% of them were reclassified as "intact" after one week, whereas the other 51% remained "stable" as MCI. Secondary analyses indicated the MCI-Intact group demonstrated larger practice effects on two memory measures than their peers (p < 0.01). CONCLUSIONS: These results continue to inform us about the nature of memory deficits in MCI, and could have implications for the diagnosis and possible treatment of this amnestic condition.

Cole AR, Noble W, van Aalten L, Plattner F, Meimaridou R, Hogan D, Taylor M, LaFrancois J, Gunn-Moore F, Verkhratsky A, Oddo S, LaFerla F, Giese KP, Dineley KT, Duff K, Richardson JC, Yan SD, Hanger DP, Allan SM, Sutherland C. · Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital, Dundee, Scotland, UK. · J Neurochem. · Pubmed #17683481 No free full text.

Abstract: Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that can regulate microtubule assembly in neurons. This function of CRMP2 is regulated by phosphorylation by glycogen synthase kinase 3 (GSK3) and cyclin-dependent kinase 5 (Cdk5). Here, using novel phosphospecific antibodies, we demonstrate that phosphorylation of CRMP2 at Ser522 (Cdk5-mediated) is increased in Alzheimer's disease (AD) brain, while CRMP2 expression and phosphorylation of the closely related isoform CRMP4 are not altered. In addition, CRMP2 phosphorylation at the Cdk5 and GSK3 sites is increased in cortex and hippocampus of the triple transgenic mouse [presenilin-1 (PS1)(M146V)KI; Thy1.2-amyloid precursor protein (APP)(swe); Thy1.2tau(P301L)] that develops AD-like plaques and tangles, as well as the double (PS1(M146V)KI; Thy1.2-APP(swe)) transgenic mouse. The hyperphosphorylation is similar in magnitude to that in human AD and is evident by 2 months of age, ahead of plaque or tangle formation. Meanwhile, there is no change in CRMP2 phosphorylation in two other transgenic mouse lines that display elevated amyloid beta peptide levels (Tg2576 and APP/amyloid beta-binding alcohol dehydrogenase). Similarly, CRMP2 phosphorylation is normal in hippocampus and cortex of Tau(P301L) mice that develop tangles but not plaques. These observations implicate hyperphosphorylation of CRMP2 as an early event in the development of AD and suggest that it can be induced by a severe APP over-expression and/or processing defect.

Falangola MF, Dyakin VV, Lee SP, Bogart A, Babb JS, Duff K, Nixon R, Helpern JA. · Center for Advanced Brain Imaging, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. · NMR Biomed. · Pubmed #17451178 No free full text.

Abstract: In this study, we used MRI to analyze quantitative parametric maps of transverse (T(2)) relaxation times in a longitudinal study of transgenic mice expressing mutant forms of amyloid precursor protein (APP), presenilin (PS1), or both (PS/APP), modeling aspects of Alzheimer's disease (AD). The main goal was to characterize the effects of progressive beta-amyloid accumulation and deposition on the biophysical environment of water and to investigate if these measurements would provide early indirect evidence of AD pathological changes in the brains of these mice. Our results demonstrate that at an early age before beta-amyloid deposition, only PS/APP mice show a reduced T(2) in the hippocampus and cortex compared with wild-type non-transgenic (NTg) controls, whereas a statistically significant within-group aging-associated decrease in T(2) values is seen in the cortex and hippocampus of all three transgenic genotypes (APP, PS/APP, and PS) but not in the NTg controls. In addition, for animals older than 12 months, we confirmed our previous report that only the two genotypes that form amyloid plaques (APP and PS/APP) have significantly reduced T(2) values compared with NTg controls. Thus, T(2) changes in these AD models can precede amyloid deposition or even occur in AD models that do not deposit beta-amyloid (PS mice), but are intensified in the presence of amyloid deposition.

Gray AJ, Sakaguchi G, Shiratori C, Becker AG, LaFrancois J, Aisen PS, Duff K, Matsuoka Y. · Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA. · Neuroreport. · Pubmed #17314674 No free full text.

Abstract: Accumulation of amyloid beta in the brain is a pathological hallmark of Alzheimer's disease, and the reduction of amyloid beta has been proposed as a primary therapeutic target. Mice immunized against amyloid beta and mice infused with anti-amyloid beta antibody (active and passive immunization, respectively) have reduced brain amyloid beta levels, and two mechanisms have been proposed: microglial phagocytosis in the brain and enhancement of amyloid beta efflux by antibodies present in the periphery (sequestration). The optimal antibody for microglial phagocytosis has been shown to be N-terminal-specific antibody; however, the potency of C-terminal-specific antibody in sequestration remains unclear. In this study, we found that anti-amyloid beta 40-specific antibody induces amyloid beta sequestration. These results indicate that C-terminal antibodies may be useful in amyloid beta sequestration therapy.

Westervelt HJ, Carvalho J, Duff K. · Brown Medical School, United States; Rhode Island Hospital, United States. · Arch Clin Neuropsychol. · Pubmed #17156971 No free full text.

Abstract: Odor identification deficits are frequently reported in Alzheimer's disease (AD) but are not universal. This study examines differences in clinical presentation in AD patients with and without odor identification impairments. Ninety patients with probable AD were administered an odor identification test as part of a neuropsychological evaluation. Variables examined included demographic information, cognitive and behavioral measures, dementia severity, neuroimaging findings, and aspects of clinical history. Defining the groups with a median split, olfactory impaired and olfactory intact patients were mostly similar, though patients with impaired odor identification performance were more likely to be male, less likely to have a family history of dementia, and had worse visuospatial functioning. The differences noted raise the possibility of a clinical subtype of the disease.

Duff K, Langbehn DR, Schoenberg MR, Moser DJ, Baade LE, Mold J, Scott JG, Adams RL. · Department of Psychiatry, University of Iowa, Iowa City, IA 52242-1000, USA. · Am J Geriatr Psychiatry. · Pubmed #17068320 No free full text.

Abstract: OBJECTIVE: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), a recently developed cognitive assessment instrument, has been shown to be useful with a variety of neuropsychiatric conditions, but its factor structure has not been examined. METHOD: Using 824 community-dwelling elders, the RBANS was examined with confirmatory and exploratory factor analyses. RESULTS: The existing structure of the RBANS was not supported; however, a two-factor solution was. CONCLUSIONS: Clinicians and researchers using the RBANS should be cautious when interpreting this measure with its existing structure.

Soreghan BA, Lu BW, Thomas SN, Duff K, Rakhmatulin EA, Nikolskaya T, Chen T, Yang AJ. · Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA. · J Alzheimers Dis. · Pubmed #16340081 No free full text.

Abstract: Increasing evidence suggests that oxidative injury is involved in the pathogenesis of many age-related neurodegenerative disorders, including Alzheimer's disease (AD). Identifying the protein targets of oxidative stress is critical to determine which proteins may be responsible for the neuronal impairments and subsequent cell death that occurs in AD. In this study, we have applied a high-throughput shotgun proteomic approach to identify the targets of protein carbonylation in both aged and PS1 + AbetaPP transgenic mice. However, because of the inherent difficulties associated with proteomic database searching algorithms, several newly developed bioinformatic tools were implemented to ascertain a probability-based discernment between correct protein assignments and false identifications to improve the accuracy of protein identification. Assigning a probability to each identified peptide/protein allows one to objectively monitor the expression and relative abundance of particular proteins from diverse samples, including tissue from transgenic mice of mixed genetic backgrounds. This robust bioinformatic approach also permits the comparison of proteomic data generated by different laboratories since it is instrument- and database-independent. Applying these statistical models to our initial studies, we detected a total of 117 oxidatively modified (carbonylated) proteins, 59 of which were specifically associated with PS1 + AbetaPP mice. Pathways and network component analyses suggest that there are three major protein networks that could be potentially altered in PS1 + AbetaPP mice as a result of oxidative modifications. These pathways are 1) iNOS-integrin signaling pathway, 2) CRE/CBP transcription regulation and 3) rab-lyst vesicular trafficking. We believe the results of these studies will help establish an initial AD database of oxidatively modified proteins and provide a foundation for the design of future hypothesis driven research in the areas of aging and neurodegeneration.

Bell KF, Ducatenzeiler A, Ribeiro-da-Silva A, Duff K, Bennett DA, Cuello AC. · Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Osler Promenade, Montreal, Que., Canada, H3G 1Y6. · Neurobiol Aging. · Pubmed #16271419 No free full text.

Abstract: Past studies using transgenic models of early-staged amyloid pathology, have suggested that the amyloid pathology progresses in a neurotransmitter-specific manner where cholinergic terminals appear most vulnerable, followed by glutamatergic terminals and finally by somewhat more resistant GABAergic terminals. To determine whether this neurotransmitter-specific progression persists at later pathological stages, presynaptic bouton densities, and the areas of occupation and localization of plaque adjacent dystrophic neurites were quantified in 18-month-old APP(K670N, M671L)+PS1(M146L) doubly transgenic mice. Quantification revealed that transgenic animals had significantly lower cholinergic, glutamatergic and GABAergic presynaptic bouton densities. Cholinergic and glutamatergic dystrophic neurites appear to be heavily influenced by fibrillar Abeta as both types displayed a decreasing area of occupation with respect to increasing plaque size. Furthermore, cholinergic dystrophic neurites reside in closer proximity to plaques than glutamatergic dystrophic neurites, while GABAergic dystrophic neurites were minimal regardless of plaque size. To investigate whether similarities exist in the human AD pathology, a monoclonal antibody (McKA1) against the human vesicular glutamate transporter 1 (VGluT1) was developed. Subsequent staining in AD brain tissue revealed the novel presence of glutamatergic dystrophic neurites, to our knowledge the first evidence of a structural glutamatergic deficit in the AD pathology.

Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Näslund J, Mathews PM, Cataldo AM, Nixon RA. · Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA. · J Cell Biol. · Pubmed #16203860 links to  free full text

Abstract: Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before beta-amyloid (Abeta) deposits extracellularly in the presenilin (PS) 1/Abeta precursor protein (APP) mouse model of beta-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Abeta. Purified AVs contain APP and beta-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent gamma-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Abeta production. Our results, therefore, link beta-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

Kumar-Singh S, Pirici D, McGowan E, Serneels S, Ceuterick C, Hardy J, Duff K, Dickson D, Van Broeckhoven C. · Department of Molecular Genetics VIB8, Neurodegenerative Brain Diseases Research Group, Molecular Neuropathology Project, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. · Am J Pathol. · Pubmed #16049337 links to  free full text

Abstract: Occurrence of amyloid beta (Abeta) dense-core plaques in the brain is one of the chief hallmarks of Alzheimer's disease (AD). It is not yet clear what factors are responsible for the aggregation of Abeta in the formation of these plaques. Using Tg2576 and PSAPP mouse models that exhibit age-related development of amyloid plaques similar to that observed in AD, we showed that approximately 95% of dense plaques in Tg2576 and approximately 85% in PSAPP mice are centered on vessel walls or in the immediate perivascular regions. Stereoscopy and simulation studies focusing on smaller plaques suggested that vascular associations for both Tg2576 and PSAPP mice were dramatically higher than those encountered by chance alone. We further identified ultrastructural microvascular abnormalities occurring in association with dense plaques. Although occurrence of gross cerebral hemorrhage was infrequent, we identified considerable infiltration of the serum proteins immunoglobulin and albumin in association with dense plaques. Together with earlier evidence of vascular clearance of Abeta, our data suggest that perturbed vascular transport and/or perivascular enrichment of Abeta leads to the formation of vasocentric dense plaques in Tg2576 and PSAPP mouse models of AD.

Falangola MF, Lee SP, Nixon RA, Duff K, Helpern JA. · Center for Advanced Brain Imaging, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. · Neurochem Res. · Pubmed #15895823 No free full text.

Abstract: This study confirms the presence of iron, co-localized with Abeta plaques, in PS/APP mouse brain, using Perls' stain for Fe3+ supplemented by 3,3'-diaminobenzidine (DAB) and Abeta immunohistochemistry in histological brains sections fixed with formalin or methacarn. In this study, the fixation process and the slice thickness did not interfere with the Perls' technique. The presence of iron in beta-amyloid plaques in PS/APP transgenic mice, a model of Alzheimer's disease (AD) pathology, may explain previous reports of reductions of transverse relaxation time (T2) in MRI studies and represent the source of the intrinsic Abeta plaque MR contrast in this model.