Amyloid precursor protein gene isoforms in Alzheimer’s disease and other neurodegenerative disorders (original) (raw)
Amyloid precursor protein mRNA levels in Alzheimer's disease brain
Molecular Brain Research, 2004
Insoluble h-amyloid deposits in Alzheimer's disease (AD) brain are proteolytically derived from the membrane bound amyloid precursor protein (APP). The APP gene is differentially spliced to produce isoforms that can be classified into those containing a Kunitz-type serine protease inhibitor domain (K + , APP 751 , APP 770 , APRP 365 and APRP 563 ), and those without (K À , APP 695 and APP 714 ,). Given the hypothesis that Ah is a result of aberrant catabolism of APP, differential expression of mRNA isoforms containing protease inhibitors might play an active role in the pathology of AD. We took 513 cerebral cortex samples from 90 AD and 81 control brains and quantified the mRNA isoforms of APP with TaqMank real-time RT-PCR. After adjustment for age at death, brain pH and gender we found a change in the ratio of KPI+ to KPI À mRNA isoforms of APP. Three separate probes, designed to recognise only KPI+ mRNA species, gave increases of between 28% and 50% in AD brains relative to controls ( p = 0.002). There was no change in the mRNA levels of KPI-(APP 695) ( p = 0.898). Therefore, whilst KPI-mRNA levels remained stable the KPI + species increased specifically in the AD brains. D
Differential brain expression of the Alzheimer's amyloid precursor protein
The EMBO Journal, 1989
The expression of the Alzheimer amyloid protein precursor (AAPP) was examined in human, monkey, dog and rat brains. Two proteins, one identified as AAPP695 and the other as AAPP751, were immunoprecipitated from the in vitro translation of human, dog and rat brain polysomes. The AAPP75, to AAPP695 ratio was highest in human, intermediate in dog and lowest in rat brain polysomes. Human cerebral cortex contained higher levels of the AAPP751 mRNA than either dog or rat cortex. AAPP695 was detected in both cerebral cortex and cerebellum of all species examined. In contrast, AAPP751 was detected predominantly in the cortex of human, monkey and to a lesser extent dog brains while it was not detected in rat brain. These findings indicate that the amyloid precursors are differentially expressed in different mammalian brains and suggest that AAPP751 is mainly expressed in the brain regions involved in plaque formation. Key words: Alzheimer's disease/amyloid precursor protein/ immunoblotting/in vitro translation/protein expression Dayan, 1971; Vaughn and Peters, 1981; Selkoe et al., 1987). The absence of AP amyloid depositions in rat could be related to their shorter lifespan or to differences in the expression and/or processing of the AAPP in the rat brain compared to mammals with longer lifespans. In the present study we used anti-AAPP antisera to study the expression of the AP precursors in the cortex and cerebellum of human, monkey, dog and rat brains.
A novel mutation in the ?-protein coding region of the amyloid ?-protein precursor (APP) gene
Human Genetics, 1992
: Subacute spongiform encephalopathy. Spongiform cerebral atrophy. Neurology, 13, 6, 455 -463. Brun A, Gottfries C G, and Roos B E (1971): Studies of the monoamine metabolism in the central nervous system in Jacob-Creutzfeldt disease. Acta Neurol. Scandinav. 47, 642 -645. Sulg I A and Brun A (1972): Spongiform encephalopathi återspeglad i EEG och patohistologi. Föredrag Medicinska Riksstämman, Hygiea. Stockholm 231. Mark J and Brun A (1973): Chromosomal deviations in Alzheimer's disease compared to those in senescence and senile dementia. Ger Clin 15, 253-258. Brun A (1973). Downs' syndrom -utvecklingsstörning och demens. Läkartidningen 80, 10, pp 936. Brun A (1974): Den presenila demensens patologi relaterad till cerebralt blodflöde. Svenska läkartidningen 71, 13, 1974: Svenska läkarsällskapets endagssymposium 73-11-07 över temat demens. Patofysiologi och klinik. 71, 1290 -1291. Brun A. and L.Gustafson (1974): Extent and severity of cerebral lesions related to clinical and regional cerebral blood flow in presenile dementia. In: PPProc of the V11th Intnl Congr of Neuropathology, Akademiai Kiado, Budapest 1974, p44. Gustafson L, D.H.Ingvar and A. Brun (1975): Clinical and neurocirculatory findings in presenile dementia related to neuropathological changes. In proc. of 2nd Intnl congr of CIANS Prague 1975. p. 371 Brun A, L Gustafson, DHI Ingvar (1974/5): Neuropathological findings related to Neuropsychiatric symptoms and regional cerebral blood flow in presenile dementia. Excerpta medica, Amsterdam, Akademiai Kiado, Budapest. Pp 101-5. Brun, A. and Gustafson, L. (1976). Distribution of cerebral degeneration in Alzheimer's disease. A clinico-pathological study. Arch Psychiatr Nervenkr, 223, 15-33. Gustafson L, Brun A and Ingvar D H (1975): Clinical and neurocirculatory findings in presenile dementia related to neuropathological changes. Activ nerv Sub (Praha) 19, 2, 351 -354. Gustafson L, A Brun, DHI Ingvar (1977): Presenile dementia: Clinical symptoms, pathoanatomical findings and cerebral blood flow. Cerebral vascular disease. A Brun, E Englund (1980): degeneration av hjärnans vita substans vid demens. Riksstämman, Hygiea. P 213 Risberg J, Brun A, Johansson M and Gustafson L (1983): Differential diagnosis of dementia by rCBF and psychometric methods. J Cer Blood Flow and Metabolism, 3, 1, Raven Press, New York, 496 -497. + abstr Brun A and Dictor M (1981): Senile plaques and tangles in dialysis dementia. Acta Path. Microbiol Scand Sect A, 89, 193-198. Brun, A. and Englund, E. (1981). Regional pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading. Histopathology, 5, 549-564. Englund E and Brun A (1981): Senile dementia -a structural basis for etiological and therapeutic considerations. Biological Psychiatry. Eds: C Perris and B Jonsson. Elsevier/North Holland Biomed Press 951 -956. Westermark P, Shirahama T, Skinner M, Brun A, Cameron R and Cohen A (1982): Immunohistochemical evidence for the lack of amyloid component in some intracrebral amyloids. Laboratory Investigation 5, 457 -460. Shirhama T, Skinner M, Westermark P, Rubinow A, Cohen A S, Brun A and Kemper T H (1982): Senile cerebral amyloid. Prealbumin as a common constituent in the neuritic plaques, in the neurofibrillary tangle and in the microangiopathic lesion. Am J Pathol 107, 41-50. Brun A (1982): Strukturellt underlag vid organisk senil demens. Symposium Sandoz: Demenstillstånd -synpunkter på etiologi och behandling, 23 -34. Brun A (1982): Alzheimer's disease and its clinical implications. In: Geriatrics. Ed: D Platt. Springer Verlag Heidelberg, NY, 343 -390. Brun A and Englund E (1982): White matter incomplete infarction in dementia. Abstract 9th Internat. Congr. Neuropath. 201. Brun A, L Gusrafson (1983). Down's syndrom -utvecklingsstörning och demens. Läkartidningen 80, 10, pp 936. Risberg J, Brun A, Johansson M and Gustafson L (1983): Differential diagnosis of dementia by rCBF and psychometric methods. J Cer Blood Flow and Metabolism, 3, 1, Raven Press, New York, 496 -497. Gustafson L, Brun A, Hagstadius S, Johansson M and Risberg J (1983): Evaluation of organic dementia and confusional states by rCBF, clinical and psychometric metods. Abstract: 2nd satellite symposium on: Effect of ageing on regulation of cerebral blood flow and metabolism. Eds: Sieshi and C V Loeb. European Neurology, 22, 2. S Karger Medical and Scientific Publishers, Basel. pp. Brun A (1983): Hjärnskada bakom vanliga former av demens. Forskning och Praktik, 15, 7, 103-106. Brun A (1983): An overview of light and electron microscopical changes. In: Alzheimer's disease. Ed: B Reisberg. The Free Press. New York, a division of Mac Millan Inc, 3 -47. Gustafson L, Brun A, Risberg J and Johansson M (1984): Evaluation of organic dementia by regional cerebral blood flow measurements and clinical psychometric methods. Monogr Neural Sci, 11, 111 -117. Karger, Basel. . Gustafson L, Brun A, Hagstadius S, Johansson M and Risberg J (1983): Evaluation of organic dementia and confusional states by rCBF, clinical and psychometric metods. Abstract: 2nd satellite symposium on: Effect of ageing on regulation of cerebral blood flow and metabolism. Eds: Sieshi and C V Loeb. European Neurology, 22, 2. S Karger Medical and Scientific Publishers, Basel. p 23. Brun A (1984): The neuropathological background of clinical signs and symptoms in organic dementia. 2 nd Nordic meeting in Neuropsychology. Lund Sweden. Pp 18-19. Brun A (1985): The structural development of Alzheimer's disease. Danish Medical Bulletin, 32, 1, 25 -27. Friedland R P, A Brun, T F Budinger (1985): Pathological and positron emission tomographic correlations in Alzheimer's disease. The Lancet 8422, vol. I/85, p 228. Brun A and Englund E (1985): Regional variations of cortical degeneration in Alzheimer's disease. Journal of Clinical and Experimental Neuropsychology, 7, 2, 167 Brun A and Englund E (1985): White matter changes in Alzheimer's presenile and senile dementia. In: Normal aging, Alzheimer's disease and senile dementia. Aspects on etiology, pathogenesis, diagnosis and treatment, Ed: C G Gottfries. Editions de lUniversité de Bruxelle's, 47 -50. Gustafson L, Brun A, Holmkvist-Franck A, Risberg J 1985: Regional Cerebral blood flow in degenerative frontal lobe dementia of non-Alzheimer type. Cerebr. Blood Flow Metabol. 5: 141-142. Gustafson L, A Brun, J Risberg (1985): Organic dementia: Clinical picture related to regional cerebral blood flow and neuropathologic al findings. Psychiatry vol. 2. Pp 605-611. Brun A, E Englund (1985): Alzheimer type dementia and white matter changes. Ata neurol. Scand. Vil 71. Pp 87-88. Gustafson L, A Brun, J Risberg (1985): Rating scales for diagnosis of Alzheimer´s disease and frontal lobe dementia of non-Alzheimer type. 26 Englund E, A Brun (1985): A White matter disorder common in Dementia of Alzheimer´s type. Pp 168-169. Englund E, A Brun (1985): demyelination contributes to Alzheimer´s disease. 18. Brun A, L Gustafson, E Englund (1985): Morphology of white matter, subcortical dementia in Alzheimer´s disease. Pp 79 -83. Brun A, Englund E (1986): A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol 1986;19:253-262. -Brun A and Gustafson L (1990): Clinico-pathological correlates of dementia: The pathoanatomical substrate of Alzheimer's disease. Excerpta Medica. -Gustafson L, Brun A, Cronqvist S, Dalfelt G, Risberg J, Riesenfeldt W and Rosén I (1990): Regional cerebral blod flow, MRI and BEAM in Alzheimer's disease. J Cer Blood Flow Metab, 9, 1, 543. Brun A, Gustafson L, and Risberg J (1990): A review of 20 years dementia research. Psychiatric Medicine, vol 32k 7, 781 -788. Igakushoin Tokyo Japan. Brun A (1991): Trends in neuropathological enquiry into the dementias: The late life pattern. Workshop on therapeutic and epidemiological aspects. Proc. IPA workshop, Cambridge. Brun A (1991): Dementia of frontal lobe type. Elsevier Science Publishers B V. Biological Psychiatry. Volume 2. G Racagni et al, eds. Pp 126 -127. Pinheiro T, Tapper U A S, Sturesson K, Brun A (1991): Experimental investigation into sample preparation of Alzheimer tissue specimens for nuclear microprobe analysis. Nuclear Instruments and Methods in Physics Research B 54, 186 -190. Brun A (1991): Structural and topographic aspects of degenerative dementia: aspects of degenerative dmentia. Diagnostic considerations. Internat Psychogeriatrics, vol 3, supp. Pp. 75 -83. Englund E, Brun A (1991): Neuropathology of vascular dementia. 5th Congr. Int. Psychogeriatr. Ass. (IP), Rome, Italy, August 18 -23. Brun A (1992): Alzheimer -en demenssjukdom. Vandringar med Böcker. Bibliotekstjänst, Lund. Basun H, O Almquist, K Axelman , A Brun, T A Campbell, J Collinge, C Forsell . S Froelich , L-O Wahlund, L Wetterberg, L Lannfeldt (1997). Clinical characteristics of a family with chromosome 17 -linked rapidly progressive frontotemporal dementia . Arch Neurol, 54 : 539 -544 . Liu X and A Brun (1996): Regional and laminar synaptic pathology in frontal lobe degeneration of non-Alzheimer type. Int. J. Ger. Psych.11, 47-55. Liu X, C Erikson, A Brun (1996). Cortical synaptic changes and gliosis in normal aging, Alzheimer´s disease and frontal lobe degeneration. Dementia 7, 128-134. A 136 Brun A and Passant U (1996): Frontal lobe degeneration of non-Alzheimer type. Structural changes, diagnostic criteria and relation to other fronto-temporal dementias. Acta Neurol.Scand. Suppl 168 28 -30 . A Swedish state of the art document on dementia diseases .Eds L -O Wahlund , B Winblad . Ohlsson Y. A Brun, E Englund (1996): Fundamental pathological lesions in vascular dementia . Acta Neurol Scand Suppl 168, 31-38.A Swedish state of the art document on dementia diseases. ( 1997 ): Misclassification of dementia subtype using the Hachinski ischemic score : results of a meta-analysis of patients with pathologically verified dementias . Annals New York Academy of Sciences. 490 -492....
Altered expression of genes for amyloid and cytoskeletal proteins in alzheimer cortex
Annals of Neurology, 1989
Recent studies have indicated a normal gene dose for the amyloid precursor protein (APP) in Alzheimer's disease (AD). These findings leave open the possibility that elevated levels of messenger RNA (mRNA) for this protein may contribute to the pathogenesis of AD. Using Northern analysis, we compared the levels of mRNA for the APP and 3 cytoskeletal proteins in parietal cortex of 6 brains having marked AD-type degeneration with the levels of these mRNAs in 6 control samples. The cytoskeletal mRNAs studied were those for the human neurofilament 68-kDa subunit (HNFL), for α-tubulin, and for glial fibrillary acidic protein (GFAP). A ribonuclease (RNase) protection assay was also used to compare AD and control HNFL mRNA levels. The mRNAs for APP, HNFL, and α-tubulin were diminished in AD cortex. The decrement for APP mRNA was less than that for HNFL or α-tubulin. The message for GFAP in AD cortex showed no loss. The findings support a general deficit in neuronal mRNAs, including that for APP. They do not exclude the possibility of elevated levels of the message for the APP in small neuronal subsets, in subcortical neurons projecting to cortex, or as a generalized phenomenon in earlier stages of the disease.
Journal of Biological Chemistry, 1998
Although a number of studies have examined amyloid precursor protein (APP) mRNA levels in Alzheimer's disease (AD), no clear consensus has emerged as to whether the levels of transcripts for isoforms containing a Kunitz protease inhibitory (KPI)-encoded region are increased or decreased in AD. Here we compare AD and control brain for the relative amounts of APP protein containing KPI to APP protein lacking this domain. APP protein was purified from the soluble subcellular fraction and Triton X-100 membrane pellet extract of one hemisphere of AD (n ؍ 10), normal (n ؍ 7), and neurological control (n ؍ 5) brains. The amount of KPI-containing APP in the purified protein samples was determined using two independent assay methods. The first assay exploited the inhibitory action of KPI-containing APP on trypsin. The second assay employed reflectance analysis of Western blots. The proportion of KPI-containing forms of APP in the soluble subcellular fraction of AD brains is significantly elevated (p < 0.01) compared with controls. Species containing a KPI domain comprise 32-41 and 76 -77% of purified soluble APP from control and AD brains, respectively. For purified membraneassociated APP, 72-77 and 65-82% of control and AD samples, respectively, contain a KPI domain. Since KPIcontaining species of APP may be more amyloidogenic (Ho, L., Fukuchi, K., and Yonkin, S. G. (1996) J. Biol. Chem. 271, 30929 -30934), our findings support an imbalance of isoforms as one possible mechanism for amyloid deposition in sporadic AD.
Altered gene expression and neuropathology in Alzheimer's disease
Neurobiology of Aging, 2006
In their review article published in this issue of Neurobiology of Aging, Reddy and McWeeney provide an overview on the neuropathology of Alzheimer's disease (AD), genes related to AD, transgenic animal models of AD, and results from studies which have focused on alterations in gene expression in AD, performed both on postmortem brains from patients with AD and controls as well as on transgenic mouse models of this disease. Their major conclusion is that findings from studies carried out to date on alterations in gene expression in AD are still limited in terms of their utility in treating AD patients and in developing early methods of detection. We generally agree with most of the ideas and trajectories of Reddy and McWeeney . However, we would like to draw attention to the following issues.
Molecular Brain Research, 1993
Studies comparing the expression of the amyloid/3 protein precursor (APP) gene in brains of patients with Alzheimer's disease (AD) and control individuals have resulted in contradictory findings indicative of selective reductions and relative increases of APP alternative transcripts in AD brain. It has been suggested that changes in APP expression in relation to AD neuropathology may represent highly specific and localized events involving only select populations of cells in particular brain regions. For example, reported AD-related alterations in ratios of APP alternative transcripts could be attributed to changes in expression of APP in specific neuronal subpopulations, and/or reactive astrocytes and/or microglia. To address this question, we have employed in situ hybridization using biotinylated oligonucleotide probes designed to localize specific APP mRNA transcripts in the hippocampal formation of AD patients and age-matched controls since this method allows a clear distinction of the classes of neurons and glia containing a particular message. Our findings can be summarized as follows: (1) APP695 and APP751 mRNAs are made primarily by pyramidal neurons in both AD and age-matched control hippocampal sections, (2) the cellular specificity and regional distribution of these messages are extremely similar not only with respect to each other, but also in AD and control hippocampal formation, (3) glial cells appear to contain only small or negligible amounts of APP message, and even in affected regions of AD brain displaying marked gliosis, reactive astrocytes do not contain increased amounts of APP RNA, and (4) APP695 and APP751 mRNAs were localized to both the soma and neuronal processes of neurons but dendritic staining for both messages appeared to be less pronounced in the AD cases.
The Journal of Comparative Neurology, 1994
The P-amyloid or A4 protein is found deposited in neuritic plaques and neurofibrillary tangles in Alzheimer's disease (AD) affected brains and in the brains of adults with Down's Syndrome. The precursor to this 42 amino acid protein is the 695 amino acid long amyloid protein precursor (APP-695). Two additional APP species, APP-751 and APP-770, each contain a 56-amino-acid insert sequence that is analogous to Kunitz protease inhibitors. APP mRNA is widely distributed in both the human and rat brain, although the adult rat does not develop mature amyloid pathology. In this study we used antibodies against the N-terminus, junction site (unique to APP-695) insert sequence (unique to APP-751,-770), A4 region, and C-terminus of APP to immunolabel sections from throughout the young adult rat brain. From these results we constructed maps of the staining pattern of each antibody. We found that APP is widely distributed throughout the brain, that labelling is predominantly neuronal in character, and that there is marked variation among the antibodies in the extent of labelling, the particular cell populations stained, and the structures labelled within individual cells. The differential staining patterns observed with the five different antibodies suggest that the way APP is processed differs from one region to another and within different compartments in the cell. The specificity of the antibodies was established by Western blot analysis, in which APP species of approximately 95 and 110 kD were found. Our findings on the distribution of APP provide a foundation for further investigations into the normal role of APP and the pathogenesis of AD.
Background Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by a progressive loss of higher cognitive functions. The brain of an individual with AD exhibits extracellular senile plaques (SPs) of aggregated amyloid-beta peptide (Aβ) and intracellular neurofibrillary tangles (NFTs). Given the critical role of neuronal transport of both proteins and organelles, it is not surprising that perturbation of microtubule-based transport may play a major role in the pathogenesis of AD.Materials and methods We used the cDNA subtraction methodology and in vitro neural cell culture analyses to study the meaning of the brain site-specific gene expression pattern in cerebral tissue obtained from AD patients and also from control subjects at autopsy.Results We observed that cytoskeleton-associated proteins were down-regulated in AD subjects. We also noted an altered expression of the microtubule-associated protein 1B (MAP1B), the heat-shock protein (HSP)-90 (a key chaperone molecule), the tripartite motif-containing proteins (TRIM)-32/37 (an anti apoptotic enzyme with ubiquitin-protein ligase activity) and the Reticulon-3 (a modulator of the amyloid-precursor-protein (APP) cleavage) in AD brains. Additional molecular- and cell-biological studies revealed that small interfering RNA (siRNA)-mediated down-regulation of MAP1B expression leads to neuronal cell death in vitro.Conclusion Altered expression of MAP1B, HSP90, TRIM32/37 and Reticulon-3 provides new clues by which the ubiquitin-proteasome-, the protein-chaperon- and the APP-processing systems are disturbed in AD, thus, leading to neuritic amyloid plaques and neurofibrillary tangles.