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1.
Langmuir ; 25(8): 4564-70, 2009 Apr 21.
Article in English | MEDLINE | ID: mdl-19281272

ABSTRACT

Cellular adhesion and growth on solid-state surfaces is the central theme in the development of cell-based biosensors and implantable medical devices. Suitable interface techniques must be applied to construct stable and well-organized thin films of biologically active molecules that would control the development of neuronal cells on chips. Peptides such as RGD fragments, poly-L-lysine (PLL), or basal lamina proteins, such as laminin or fibronectin, are often used in order to promote cellular adhesion on surfaces. In this paper we describe the characterization of several self-assembled monolayers (SAMs) for their ability to anchor a laminin-derived synthetic peptide, PA22-2, a peptide known to promote neuronal attachment and stimulate neurite outgrowth. We have evaluated the immobilization of PA22-2 onto 16-mercaptohexadecanoic acid, 4-maleimide-N-(11-undecyldithio)butanamide, and 2-(maleimide)ethyl-N-(11-hexaethylene oxide-undecyldithio)acetamide SAM functionalized Au substrates. The neuronal attachment and outgrowth have been evaluated in embryonic mouse hippocampal neuron cultures up to 14 days in vitro. Our results show that differences in the cell morphologies were observed on the surfaces modified with various SAMs, despite the minor differences in chemical composition identified using standard characterization tools. These different cell morphologies can most probably be explained when investigating the effect of a given SAM layer on the adsorption of proteins present in the culture medium. More likely, it is the ratio between the specific PA22-2 adsorption and nonspecific medium protein adsorption that controls the cellular morphology. Large amounts of adsorbed medium proteins could screen the PA22-2 sites required for cellular attachment.


Subject(s)
Neurons/metabolism , Peptides/chemistry , Sulfhydryl Compounds/chemistry , Adsorption , Animals , Cell Adhesion , Chemistry/methods , Culture Media/chemistry , Culture Media/metabolism , Hippocampus/metabolism , Mice , Models, Chemical , Oligopeptides/chemistry , Spectroscopy, Fourier Transform Infrared , Surface Properties
2.
Article in English | MEDLINE | ID: mdl-19163039

ABSTRACT

Extracellular, high signal-to-noise ratio recordings from electrogenic cells require a tight coupling between the cellular membrane and the recording electrode. Self assembled monolayers (SAMs) of alkanethiols functionalized with peptides were used in combination with micro- and nano-structured features on the sensor surface. This combination of surface chemistry and topography triggers a phagocytosis-like engulfment and ensures tight coupling. In this paper we report the results concerning usage of different SAMs and the influence of the peptide concentration towards cell adhesion and outgrowth. Later on, the optimized peptide functionalized SAMs were applied on micro- and nano-structured sensor surfaces. As a result, phagocytosis-like events could be shown using focused ion beam SEM and confocal fluorescence imaging.


Subject(s)
Biosensing Techniques , Neurons/cytology , Peptides , Alkanes , Animals , Biomedical Engineering , Cell Adhesion , Cell Line , Cell Proliferation , Cells, Cultured , Electrodes , Mice , Microscopy, Electron, Scanning , Neurons/metabolism , Sulfhydryl Compounds , Surface Properties
3.
Biochem Soc Trans ; 33(Pt 4): 559-62, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16042544

ABSTRACT

Presenilin 1 plays a central catalytic role in the gamma-secretase processing of amyloid precursor protein, Notch and many other substrates. However, this core component clearly mediates independently several other physiological roles in the cell/neuron. Besides its involvement in beta-catenin degradation, we discuss here the recent implication of presenilin 1 in the turnover of the intercellular cell adhesion molecule, telencephalin, through a degradation route that bears autophagic characteristics. Activation of the endosomal/lysosomal system in general and autophagic degradation in particular, is finally briefly discussed in the context of neurodegenerative diseases.


Subject(s)
Endopeptidases/metabolism , Membrane Proteins/metabolism , Amyloid Precursor Protein Secretases , Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases , Autophagy , Cell Adhesion Molecules , Hippocampus/pathology , Humans , Membrane Glycoproteins/metabolism , Nerve Degeneration/metabolism , Nerve Degeneration/pathology , Nerve Tissue Proteins/metabolism , Neurons/pathology , Phagocytosis , Presenilin-1
4.
Neuron ; 32(4): 579-89, 2001 Nov 20.
Article in English | MEDLINE | ID: mdl-11719200

ABSTRACT

The carboxyl terminus of presenilin 1 and 2 (PS1 and PS2) binds to the neuron-specific cell adhesion molecule telencephalin (TLN) in the brain. PS1 deficiency results in the abnormal accumulation of TLN in a yet unidentified intracellular compartment. The first transmembrane domain and carboxyl terminus of PS1 form a binding pocket with the transmembrane domain of TLN. Remarkably, APP binds to the same regions via part of its transmembrane domain encompassing the critical residues mutated in familial Alzheimer's disease. Our data surprisingly indicate a spatial dissociation between the binding site and the proposed catalytic site near the critical aspartates in PSs. They provide important experimental evidence to support a ring structure model for PS.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Membrane Glycoproteins/metabolism , Membrane Proteins/chemistry , Nerve Tissue Proteins/metabolism , Amyloid beta-Protein Precursor/chemistry , Animals , Binding Sites , Cell Differentiation , Gene Expression , Hippocampus/cytology , Membrane Glycoproteins/chemistry , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Knockout , Nerve Tissue Proteins/chemistry , Neurons/cytology , Neurons/metabolism , Presenilin-1 , Presenilin-2 , Protein Structure, Tertiary , Two-Hybrid System Techniques
6.
J Neurochem ; 78(5): 1168-78, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11553691

ABSTRACT

The gamma-secretase cleavage is the last step in the generation of the beta-amyloid peptide (Abeta) from the amyloid precursor protein (APP). The Abeta precipitates in the amyloid plaques in the brain of Alzheimer's disease patients. The fate of the intracellular APP carboxy-terminal stub generated together with Abeta has been, in contrast, only poorly documented. The analogies between the processing of APP and other transmembrane proteins like SREBP and Notch suggests that this intracellular fragment could have important signalling functions. We demonstrate here that APP-C59 is rapidly degraded (half-life approximately 5 min) when overexpressed in baby hamster kidney cells or primary cultures of neurones by a mechanism that is not inhibited by endosomal/lysosomal or proteasome inhibitors. Furthermore, APP-C59 binds to the DNA binding protein Fe65, although this does not increase the half-life of APP-C59. Finally, we demonstrate that a fraction of APP-C59 becomes redistributed to the nuclear detergent-insoluble pellet, in which the transcription factor SP1 is also present. Overall our results reinforce the analogy between Notch and APP processing, and suggest that the APP intracellular domain, like the Notch intracellular domain, could have a role in signalling events from the plasma membrane to the nucleus.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Cell Nucleus/enzymology , Endopeptidases/metabolism , Neurons/enzymology , Amyloid Precursor Protein Secretases , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Aspartic Acid Endopeptidases , Cell Fractionation , Cells, Cultured , Cricetinae , Cytoplasm/metabolism , Genetic Vectors , Kidney/cytology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Knockout , Neurons/cytology , Presenilin-1 , Receptors, Notch , Semliki forest virus/genetics , Sp1 Transcription Factor/metabolism , Subcellular Fractions , Transfection
7.
J Cell Biol ; 154(4): 731-40, 2001 Aug 20.
Article in English | MEDLINE | ID: mdl-11502763

ABSTRACT

We investigated the relationship between PS1 and gamma-secretase processing of amyloid precursor protein (APP) in primary cultures of neurons. Increasing the amount of APP at the cell surface or towards endosomes did not significantly affect PS1-dependent gamma-secretase cleavage, although little PS1 is present in those subcellular compartments. In contrast, almost no gamma-secretase processing was observed when holo-APP or APP-C99, a direct substrate for gamma-secretase, were specifically retained in the endoplasmic reticulum (ER) by a double lysine retention motif. Nevertheless, APP-C99-dilysine (KK) colocalized with PS1 in the ER. In contrast, APP-C99 did not colocalize with PS1, but was efficiently processed by PS1-dependent gamma-secretase. APP-C99 resides in a compartment that is negative for ER, intermediate compartment, and Golgi marker proteins. We conclude that gamma-secretase cleavage of APP-C99 occurs in a specialized subcellular compartment where little or no PS1 is detected. This suggests that at least one other factor than PS1, located downstream of the ER, is required for the gamma-cleavage of APP-C99. In agreement, we found that intracellular gamma-secretase processing of APP-C99-KK both at the gamma40 and the gamma42 site could be restored partially after brefeldin A treatment. Our data confirm the "spatial paradox" and raise several questions regarding the PS1 is gamma-secretase hypothesis.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Cell Compartmentation , Endopeptidases/metabolism , Membrane Proteins/metabolism , Neurons/metabolism , Protein Processing, Post-Translational , Amyloid Precursor Protein Secretases , Amyloid beta-Protein Precursor/isolation & purification , Animals , Aspartic Acid Endopeptidases , Cells, Cultured , Endopeptidases/isolation & purification , Endoplasmic Reticulum , Golgi Apparatus , Membrane Proteins/isolation & purification , Mice , Mutation , Neurons/cytology , Neurons/ultrastructure , Presenilin-1 , Protein Transport/genetics
8.
J Biol Chem ; 276(46): 42645-57, 2001 Nov 16.
Article in English | MEDLINE | ID: mdl-11526104

ABSTRACT

Urea-based beta-amyloid (Abeta) SDS-polyacrylamide gel electrophoresis and immunoblots were used to analyze the generation of Abeta peptides in conditioned medium from primary mouse neurons and a neuroglioma cell line, as well as in human cerebrospinal fluid. A comparable and highly conserved pattern of Abeta peptides, namely, 1-40/42 and carboxyl-terminal-truncated 1-37, 1-38, and 1-39, was found. Besides Abeta1-42, we also observed a consistent elevation of amino-terminal-truncated Abeta2-42 in a detergent-soluble pool in brains of subjects with Alzheimer's disease. Abeta2-42 was also specifically elevated in cerebrospinal fluid samples of Alzheimer's disease patients. To decipher the contribution of potential different gamma-secretases (presenilins (PSs)) in generating the amino-terminal- and carboxyl-terminal-truncated Abeta peptides, we overexpressed beta-amyloid precursor protein (APP)-trafficking mutants in PS1+/+ and PS1-/- neurons. As compared with APP-WT (primary neurons from control or PS1-deficient mice infected with Semliki Forest virus), PS1-/- neurons and PS1+/+ neurons overexpressing APP-Deltact (a slow-internalizing mutant) show a decrease of all secreted Abeta peptide species, as expected, because this mutant is processed mainly by alpha-secretase. This drop is even more pronounced for the APP-KK construct (APP mutant carrying an endoplasmic reticulum retention motif). Surprisingly, Abeta2-42 is significantly less affected in PS1-/- neurons and in neurons transfected with the endocytosis-deficient APP-Deltact construct. Our data confirm that PS1 is closely involved in the production of Abeta1-40/42 and the carboxyl-terminal-truncated Abeta1-37, Abeta1-38, and Abeta1-39, but the amino-terminal-truncated and carboxyl-terminal-elongated Abeta2-42 seems to be less affected by PS1 deficiency. Moreover, our results indicate that the latter Abeta peptide species could be generated by a beta(Asp/Ala)-secretase activity.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/biosynthesis , Amyloid beta-Peptides/cerebrospinal fluid , Amyloid beta-Peptides/chemistry , Peptide Fragments/biosynthesis , Peptide Fragments/cerebrospinal fluid , Peptide Fragments/chemistry , Aged , Aged, 80 and over , Alzheimer Disease/cerebrospinal fluid , Amino Acid Sequence , Amyloid Precursor Protein Secretases , Animals , Aspartic Acid Endopeptidases/metabolism , Brain/metabolism , Cell Line , Cells, Cultured , DNA, Complementary/metabolism , Electrophoresis, Gel, Two-Dimensional , Electrophoresis, Polyacrylamide Gel , Endopeptidases , Endoplasmic Reticulum/metabolism , Humans , Immunoblotting , Mice , Mice, Knockout , Middle Aged , Molecular Sequence Data , Mutation , Neurons/metabolism , Peptides/chemistry , Precipitin Tests , Protein Binding , Protein Structure, Tertiary , Semliki forest virus/genetics , Sequence Homology, Amino Acid , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
9.
Hum Mol Genet ; 10(16): 1665-71, 2001 Aug 01.
Article in English | MEDLINE | ID: mdl-11487570

ABSTRACT

Release of amyloid beta (Abeta) from the amyloid precursor protein (APP) requires cleavages by beta- and gamma-secretases and plays a crucial role in Alzheimer's disease (AD) pathogenesis. Missense mutations in the APP gene causing familial AD are clustered around the beta-, alpha- and particular gamma-secretase cleavage sites. We systematically compare in primary neurons the effect on APP processing of a series of clinical APP mutations (two of which not characterized before) located in close proximity to the gamma-secretase cleavage site. We confirm and extend previous observations showing that all these mutations (T714I, V715M, V715A, I716V, V717I and V717L) affect gamma-secretase cleavage causing an increased relative ratio of Abeta42 to Abeta40. Taking advantage of these extended series of APP mutations we were able to demonstrate an inverse correlation between these ratios and the age at onset of the disease in the different families. In addition, a subset of mutations caused the accumulation of APP C-terminal fragments indicating that these mutations also influence the stability of APP C-terminal fragments. However, it is unlikely that these fragments contribute significantly to the disease process.


Subject(s)
Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Endopeptidases/metabolism , Mutation , Amyloid Precursor Protein Secretases , Amyloid beta-Protein Precursor/metabolism , Animals , Aspartic Acid Endopeptidases , Binding Sites , Cells, Cultured , Electrophoresis, Polyacrylamide Gel , Humans , Mice , Neurons/metabolism , Peptide Fragments/metabolism , Precipitin Tests , Transduction, Genetic
10.
Amyloid ; 8(2): 124-42, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11409035

ABSTRACT

The extracellular deposition of short amyloid peptides in the brain of patients is thought to be a central event in the pathogenesis of Alzheimer's Disease. The generation of the amyloid peptide occurs via a regulated cascade of cleavage events in its precursor protein, A beta PP. At least three enzymes are responsible for A beta PP proteolysis and have been tentatively named alpha-, beta- and gamma-secretases. The recent identification of several of these secretases is a major leap in the understanding how these secretases regulate amyloid peptide formation. Members of the ADAM family of metalloproteases are involved in the non-amyloidogenic alpha-secretase pathway. The amyloidogenic counterpart pathway is initiated by the recently cloned novel aspartate protease named BACE. The available data are conclusive and crown BACE as the long-sought beta-secretase. This enzyme is a prime candidate drug target for the development of therapy aiming to lower the amyloid burden in the disease. Finally, the gamma-secretases are intimately linked to the function of the presenilins. These multi-transmembrane domain proteins remain intriguing study objects. The hypothesis that the presenilins constitute a complete novel type of protease family, and are cleaving A beta PP within the transmembrane region, remains an issue of debate. Several questions remain unanswered and direct proof that they exert catalytic activity is still lacking. The subcellular localization of presenilins in neurons, their integration in functional multiprotein complexes and the recent identification of additional modulators of gamma-secretase, like nicastrin, indicate already that several players are involved. Nevertheless, the rapidly increasing knowledge in this area is already paving the road towards selective inhibitors of this secretase as well. It is hoped that such drugs, possibly in concert with the experimental vaccination therapies that are currently tested, will lead to a cure of this inexorable disease.


Subject(s)
Alzheimer Disease/drug therapy , Endopeptidases/drug effects , Endopeptidases/metabolism , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Aspartic Acid Endopeptidases/drug effects , Aspartic Acid Endopeptidases/metabolism , Humans
12.
J Biol Chem ; 276(6): 4211-7, 2001 Feb 09.
Article in English | MEDLINE | ID: mdl-11071887

ABSTRACT

The amyloid peptide is the main constituent of the amyloid plaques in brain of Alzheimer's disease patients. This peptide is generated from the amyloid precursor protein by two consecutive cleavages. Cleavage at the N terminus is performed by the recently discovered beta-secretase (Bace). This aspartyl protease contains a propeptide that has to be removed to obtain mature Bace. Furin and other members of the furin family of prohormone convertases are involved in this process. Surprisingly, beta-secretase activity, neither at the classical Asp(1) position nor at the Glu(11) position of amyloid precursor protein, seems to be controlled by this maturation step. Furthermore, we show that Glu(11) cleavage is a function of the expression level of Bace, that it depends on the membrane anchorage of Bace, and that Asp(1) cleavage can be followed by Glu(11) cleavage. Our data suggest that pro-Bace could be active as a beta-secretase in the early biosynthetic compartments of the cell and could be involved in the generation of the intracellular pool of the amyloid peptide. We conclude that modulation of the conversion of pro-Bace to mature Bace is not a relevant drug target to treat Alzheimer's disease.


Subject(s)
Aspartic Acid Endopeptidases/metabolism , Subtilisins/metabolism , Amyloid beta-Protein Precursor/metabolism , Aspartic Acid Endopeptidases/biosynthesis , Furin , Hippocampus/enzymology , Hippocampus/metabolism , Humans , Protein Processing, Post-Translational
13.
J Mol Neurosci ; 17(2): 171-81, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11816790

ABSTRACT

Signaling via notch receptors and their ligands is an evolutionary ancient and highly conserved mechanism governing cell-fate decisions throughout the animal kingdom. Upon ligand binding, notch receptors are subject to a two-step proteolysis essential for signal transduction. First, the ectodomain is removed by an enzyme cleaving near the outer-membrane surface ("site2"). Consecutively, the notch intracellular domain is liberated by a second protease cutting within the transmembrane sequence ("site3"). The intracellular domain is then transferred to the nucleus to act as a transcriptional coactivator. The proteases involved in notch receptor activation are shared with other proteins undergoing regulated intramembrane proteolysis, with intriguing parallels to APP. Specifically, site3 cleavage of Notch, as well as gamma-secretase processing of APP depend both critically on presenilins 1 and 2. Moreover, ADAM 10 and ADAM 17, the proteases proposed to perform site2 cleavage, are also the most probable candidate alpha-secretases to cleave APP. While the biological significance of APP processing remains to be further elucidated, interference with notch signaling has been shown to have severe consequences both in small animal models as well as in humans. Thus, a growing number of long known genetic syndromes like Alagille syndrome or Fallot's tetralogy can be caused by mutations of genes relevant for the notch signaling pathway. Likewise, the anticipated interference of gamma-secretase inhibitors with site3 cleavage may turn out to be a major obstacle for this therapeutic approach to Alzheimer's disease.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/metabolism , Endopeptidases/metabolism , Membrane Proteins/metabolism , Receptors, Cell Surface , Signal Transduction/genetics , Transcription Factors , ADAM Proteins , ADAM17 Protein , Alzheimer Disease/physiopathology , Amyloid Precursor Protein Secretases , Animals , Aspartic Acid Endopeptidases , Endopeptidases/genetics , Humans , Membrane Proteins/genetics , Metalloendopeptidases/genetics , Metalloendopeptidases/metabolism , Presenilin-1 , Presenilin-2 , Receptor, Notch1
14.
Trends Neurosci ; 24(11 Suppl): S2-6, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11881741

ABSTRACT

It is widely believed that the pathogenesis of Alzheimer's disease (AD) is intimately, if not causatively, associated with the deposition of approximately 4 kDa beta-amyloid (A beta) peptides in the cerebral cortex and hippocampus of affected individuals. A beta peptides are liberated from transmembrane proteins, termed beta-amyloid precursor proteins (APP), by the concerted action of beta- and gamma-secretase(s). Whereas the identity of beta-secretase is no longer in question, the identity of gamma-secretase, which is responsible for the intramembranous processing of APP, has never been more enigmatic. Considerable evidence has accrued to impugn the presenilins (PS) as the executioners of intramembranous processing of APP. Here, we summarize these observations and review recent evidence that argues against the prevailing hypothesis that PS function as gamma-secretases.


Subject(s)
Alzheimer Disease/metabolism , Endopeptidases/genetics , Endopeptidases/metabolism , Receptors, Cell Surface , Transcription Factors , Amyloid Precursor Protein Secretases , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases , Humans , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Receptor, Notch1
17.
Neurobiol Dis ; 7(3): 135-51, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10860781

ABSTRACT

Protein-protein interactions are a molecular basis for the structural and functional organization within cells. They are mediated by a growing number of protein modules that bind peptide targets. Alterations in binding affinities can have serious consequences for some essential cellular processes. The three proteins identified to have mutations in their corresponding genes leading to presenile Alzheimer dementia (AD)-the amyloid precursor protein (APP) and presenilin 1 and 2-all interact with other proteins. The nature and function of these interacting proteins may contribute to elucidating the proper physiological functions of the AD proteins. APP-interacting proteins are pointing toward a function of APP in cell adhesion and neurite outgrowth and signaling. Proteins interacting with the presenilins however are more diverse in nature linking presenilin function to regulation in different signaling pathways including Wnt and Notch but also in apoptosis and Ca(2+) homeostasis. Further research however is still needed to delineate the exact functional relevance of these interactions with respect to the physiological functions of the AD proteins in particular and the contribution of these proteins to AD pathogenesis in general.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/metabolism , Membrane Proteins/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/physiology , Apoptosis/physiology , Cell Adhesion/physiology , Humans , Membrane Proteins/physiology , Neurites/physiology , Presenilin-1 , Presenilin-2 , Receptors, Notch , Signal Transduction/physiology
18.
J Cell Sci ; 113 ( Pt 11): 1857-70, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10806097

ABSTRACT

Recent research has identified some key players involved in the proteolytic processing of amyloid precursor protein (APP) to amyloid beta-peptide, the principal component of the amyloid plaques in Alzheimer patients. Interesting parallels exists with the proteolysis of other proteins involved in cell differentiation, cholesterol homeostasis and stress responses. Since the cytoplasmic domain of APP is anchored to a complex protein network that might function in axonal elongation, dendritic arborisation and neuronal cell migration, the proteolysis of APP might be critically involved in intracellular signalling events.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/metabolism , Amino Acid Sequence , Amyloid beta-Protein Precursor/genetics , Animals , Humans , Molecular Sequence Data
19.
Ann N Y Acad Sci ; 920: 158-64, 2000.
Article in English | MEDLINE | ID: mdl-11193144

ABSTRACT

Familial Alzheimer's disease (FAD) is now linked to at least three genes encoding the amyloid precursor protein (APP) on chromosome 21, and presenilin 1 and 2 on chromosome 14 and 1, respectively. FAD cases in whom presenilin mutations occur are more frequent than those with APP mutations. However, altogether they only account for approximately 0.1% of all the people suffering from Alzheimer's disease (AD), and the causes of the remaining 99.9% of the sporadic form of AD or senile dementia remain unknown. Since FAD presents with the same neuropathological features as sporadic AD, i.e., cognitive impairments and the amyloid plaques and tangles in the brain, our working hypothesis is that similar molecular pathogenic mechanisms underly both sporadic and familial AD. It follows that APP and the presenilins must be key players in the disease. Detailed knowledge about the cell biology of these proteins will be a rich source of insight into the pathology of AD, but will also shed light on the fundamental neurobiology of these proteins.


Subject(s)
Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Membrane Proteins/genetics , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/metabolism , Animals , Brain/metabolism , Brain/pathology , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 14 , Chromosomes, Human, Pair 21 , Humans , Membrane Proteins/metabolism , Mutation , Presenilin-1 , Presenilin-2
20.
Hum Mol Genet ; 9(2): 303-10, 2000 01 22.
Article in English | MEDLINE | ID: mdl-10607841

ABSTRACT

Mutations in the presenilin 1 ( PS-1 ) gene cause Alzheimer's disease (AD). These mutations alter the processing of the amyloid precursor protein (APP) by increasing the production of the fibrillogenic amyloid fragment, Abeta1-42/43. Since the secretase activities that process APP are localized in different intracellular compartments, it is likely that membrane transport is a key factor in the pathogenesis of AD. In this report we provide evidence for a direct connection between PS-1 and membrane transport. We show that the N-terminus of PS-1 binds to rab GDP dissociation inhibitor (rabGDI), a regulatory factor in vesicle transport. In PS-1-deficient neurons we found a 2-fold decrease in the amount of rabGDI associated with membranes. Our findings are compatible with PS-1 being a membrane receptor for rabGDI. This is in line with a role of PS-1 in the regulation of protein trafficking in the ER/Golgi, which can modulate the production of Abeta.


Subject(s)
Alzheimer Disease/metabolism , Guanine Nucleotide Dissociation Inhibitors/metabolism , Membrane Proteins/metabolism , Receptors, Cell Surface/metabolism , Adult , Animals , Biological Transport, Active/genetics , Cell Compartmentation/genetics , Cell Line , Guanine Nucleotide Dissociation Inhibitors/genetics , Humans , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice , Neurons/metabolism , Peptide Fragments/genetics , Peptide Fragments/metabolism , Presenilin-1 , Receptors, Cell Surface/genetics , Transfection
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