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PubMed2005

Amyloid imaging: from benchtop to bedside.

Tremendous efforts have been made in the search for a cure or effective treatment of Alzheimer's disease (AD) to develop therapies aimed at halting or reversing amyloid plaque deposition in the brain. This necessitates in vivo detection and quantification of amyloid plaques in the brain for efficacy evaluation of anti-amyloid therapies. For this purpose, a wide array of amyloid-imaging probes has been developed, mainly for in vivo studies based on positron emission tomography and single photon emission computed tomography. This review provides a full account of the development of amyloid-imaging agents. The in vitro binding properties and in vivo pharmacokinetic profiles of all amyloid-imaging agents so far reported are comprehensively and uniquely surveyed. Emphasis is placed on the development of small-molecule probes based on amyloid dyes, such as Congo red and thioflavin T. Compared to large biomolecules, these small-molecule probes have been systematically investigated through extensive structure activity relationship studies. Many of the probes show favorable properties for in vivo studies. As a result, three lead compounds, termed PIB (Pittsburgh-Compound B, [(11)C]6-OH-BTA-1), FDDNP (2-(1-[6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile), and SB-13 (4-N-methylamino-4'-hydroxystilbene), have been identified and evaluated in human subjects. Preliminary studies have indicated that these lead compounds exhibit a characteristic retention in AD subjects that is consistent with the AD pathology, thus proving the concept that amyloid deposits in the brain can be readily detected and quantified in vivo. The progress to date paves the way for further investigation in various aspects of AD research. Once developed, these amyloid-imaging agents could be used as biomarkers to aid in early and definitive diagnosis of AD, facilitate drug discovery and development, and allow pathophysiological studies of the disease mechanism. Furthermore, the success in the development of amyloid-imaging agents helps with the development of imaging agents for in vivo studies of other AD pathologies in particular and of neurodegenerative disorders in general.

Alzheimer Disease↗
PubMed2000

Expression of amyloid precursor protein in human astrocytes in vitro: isoform-specific increases following heat shock.

The beta-amyloid protein deposited in senile plaques and cerebral blood vessels in the Alzheimer's disease brain is derived from the larger transmembrane spanning amyloid precursor protein. The present study investigates the effects of heat shock on the expression and processing of amyloid precursor protein in a normal human fetal astrocytic cell line CC2565 using reverse transcription-polymerase chain reaction, in situ hybridization histochemistry and western blot analysis. Heat shock led to an increase in the messenger RNA encoding Kunitz protease inhibitor isoforms of amyloid precursor protein, which peaked at 4h post-heat shock. This increase was confined to the messenger RNA encoding amyloid precursor protein-751, with a decrease in amyloid precursor protein-770 and no change in amyloid precursor protein-695. This shift in splicing was accompanied by a significant decrease in secreted amyloid precursor protein and an increase in beta-secretase processing within the cell. These findings demonstrate that astrocytes in vitro demonstrate a striking response to heat shock. This is unlikely to be due to a direct action on the promoter region of the gene, since the response is specific for one splice variant; amyloid precursor protein-751 messenger RNA. This increase in expression is further accompanied by a decrease in secretion of amyloid precursor protein, implying a shift in processing towards an intracellular route, possibly via the actions of the beta-secretase enzyme, which is known to be potentially amyloidogenic. Such a mechanism may contribute to amyloidosis in the intact brain in response to cellular stress, such as head injury.

Amyloid beta-Protein Precursor↗
PubMed1994

Gastrointestinal amyloid deposits in old age. Report on 110 consecutive autopsical patients and 98 retrospective bioptic specimens.

The prevalence of gastrointestinal amyloid was determined in 110 consecutive autopsy patients aged 85 years and older. Paraffin sections from the esophagus, stomach, small intestine, colon and rectum were stained with Congo red and inspected in polarized light. Amyloid was found in 38 patients (36%). Four patients had generalized amyloidosis and the remaining 34 revealed more localized varieties of amyloid. Immunohistochemical classification with a panel of antisera directed against five major amyloid fibril proteins displayed at least four different types of amyloid. Twenty cases exhibited amyloid of transthyretin origin, five cases were of lambda light chain origin and one case was of amyloid A-type. Thus far, unclassifiable amyloid deposits were found in 18 cases, 16 of which were strictly localized in subserosal veins. This consecutive autopsy series was compared with 98 randomly-selected bioptical gastrointestinal tissues with amyloid according to distribution pattern, sex, frequency of the various types of amyloid and associated diseases.

Aged↗
PubMed1996

Localized amyloid in the menisci of the knee joint.

This is, to the best of our knowledge, the first report on amyloid deposits in menisci. Fragments of menisci gained by arthroscopy from 316 patients between 20 and 80 years of age were examined. Amyloid was found in 70% of the cases from male, as well as female patients. The amyloid amount found was always very small, but the deposits seemed to increase with age. Patients more than 50 years of age all had menisceal amyloid. Two types of deposits were observed: a)stroma-deposits in the deep central portions of the menisci (tiny dots of intensely stained amyloid and/or ill defined patches of low staining intensity) and b) surface associated deposits: band-like amyloid imbibition of the collagenous stroma immediately beneath the surface of the menisci but not deeper than 0.2 mm. In all cases, amyloid was resistant when pretreated by KMn04 and immunohistologically antisera against amyloid types AA, AB and AF were negative. 3/25 cases showed a reaction with an amyloid-lambda-antibody. We assume, that amyloid in menisci is a further type of localized senile amyloidosis.

Adult↗
PubMed2002

Affinity-based inhibition of beta-amyloid toxicity.

Strategies for interfering with protein aggregation are important for elucidating and controlling the pathologies of amyloid diseases. We have previously identified compounds that block the cellular toxicity of the beta-amyloid peptide, but the relationship between their ability to inhibit toxicity and their affinity for A beta is unknown. To elucidate this relationship, we have developed an assay capable of measuring the affinities of small molecules for beta-amyloid peptide. Our approach employs immobilized beta-amyloid peptide at low density to minimize the problems that arise from variability in the beta-amyloid aggregation state. We found that low-molecular weight (MW of 700-1700) ligands for beta-amyloid can be identified readily by using surface plasmon resonance. The best of these bound effectively (K(d) approximately 40 microM) to beta-amyloid. The affinities measured for peptides in the SPR assay correspond to results from A beta cell toxicity assays. The most potent ligands for immobilized beta-amyloid are the most potent inhibitors of the neuronal cell toxicity of beta-amyloid. Compounds with dissociation constants above approximately 100 microM did not show significant activity in the cell toxicity assays. Our data support the hypothesis that ligands exhibiting greater affinity for the beta-amyloid peptide are effective at altering its aggregation and inhibiting cell toxicity.

Amino Acid Sequence↗
PubMed1998

Characterization of the transthyretin acid denaturation pathways by analytical ultracentrifugation: implications for wild-type, V30M, and L55P amyloid fibril formation.

Analytical ultracentrifugation methods were utilized to further characterize the acid denaturation pathways of wild-type, V30M, and L55P transthyretin (TTR) that generate intermediates leading to amyloid fibril formation and possibly the diseases senile systemic amyloidosis and familial amyloid polyneuropathy. Equilibrium and velocity methods were employed herein to characterize the TTR quaternary structural requirements for amyloid fibril formation. From neutral to slightly acidic conditions (pH 7.5-5.1), wild-type transthyretin (0.2-0.3 mg/mL, 100 mM KCl, 37 degrees C) exists as a tetramer and is incapable of fibril formation. Under more acidic conditions (pH 5 to 3.9), tetrameric wild-type TTR slowly dissociates to a monomer having an alternatively folded tertiary structure(s) that self-assembles at physiological concentration (0.2 mg/mL) into a ladder of quaternary structural intermediates of increasing molecular weight. These intermediates appear to be on the pathway of amyloid fibril formation, since they ultimately disappear when amyloid fibrils are observed. The V30M and L55P TTR variants exhibit similar acid denaturation pathways, with the exception that dissociation of the tetramer to the monomeric amyloidogenic intermediate occurs at a higher pH and to a much greater extent, allowing the quaternary structural intermediates to be readily observed by velocity methods. Partial denaturation and assembly of the monomeric amyloidogenic intermediate(s) occur at pH 5.4 for V30M and L55P TTR over a 72 h period, during which wild-type TTR maintains its normal tetrameric three-dimensional structure. Interestingly, the L55P and V30M familial amyloid polyneuropathy (FAP) associated variants form amyloid protofilaments at pH 7.5 (37 degrees C) after several weeks of incubation, suggesting that the activation barriers for TTR tetramer dissociation to the monomeric amyloidogenic intermediate are much lower for the FAP variants relative to wild-type TTR, which does not form amyloid or amyloid protofilaments under these conditions. This study establishes the key role of the monomeric amyloidogenic intermediate and its self-assembly into a ladder of quaternary structural intermediates for the formation of wild-type, V30M, and L55P transthyretin amyloid fibrils.

Amyloid↗
PubMed1999

Novel effects of FCCP [carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone] on amyloid precursor protein processing.

Amyloidogenic processing of the beta-amyloid precursor protein (APP) has been implicated in the pathology of Alzheimer's disease. Because it has been suggested that catabolic processing of the APP holoprotein occurs in acidic intracellular compartments, we studied the effects of the protonophore carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) and the H+-ATPase inhibitor bafilomycin A1 on APP catabolism in human embryonic kidney 293 cells expressing either wild-type or "Swedish" mutant APP. Unlike bafilomycin A1, which inhibits beta-amyloid production in cells expressing mutant but not wild-type APP, FCCP inhibited beta-amyloid production in both cell types. Moreover, the effects of FCCP were independent of alterations in total cellular APP levels or APP maturation, and the concentrations used did not alter either cellular ATP levels or cell viability. Bafilomycin A1, which had no effect on beta-amyloid production in wild-type cells, inhibited endocytosis of fluorescent transferrin, whereas concentrations of FCCP that inhibited beta-amyloid production in these cells had no effect on endosomal function. Thus, in wild-type-expressing cells it appears that the beta-amyloid peptide is not produced in the classically defined endosome. Although bafilomycin A1 decreased beta-amyloid release from cells expressing mutant APP but not wild-type APP, it altered lysosomal function in both cell types, suggesting that in normal cells beta-amyloid is not produced in the lysosome. Although inhibition of beta-amyloid production by bafilomycin A1 in mutant cells may occur via changes in endosomal/lysosomal pH, our data suggest that FCCP inhibits wild-type beta-amyloid production by acting on a bafilomycin A1-insensitive acidic compartment that is distinct from either the endosome or the lysosome.

Adenosine Triphosphate↗
PubMed1997

Disaggregation of Alzheimer beta-amyloid by site-directed mAb.

In Alzheimer disease, beta-amyloid peptide accumulates in the brain as insoluble amyloid plaques. Amyloid filaments, similar to those found in amyloid plaques, can be assembled in vitro from chemically synthesized beta-peptides. In this study, we report that antibodies raised against the N-terminal region (1-28) of the beta-amyloid peptide bind to the in vitro-formed beta-amyloid assemblies, leading to disaggregation of the fibrils and partial restoration of the peptide's solubility. The concomitant addition of fibrillar beta-amyloid with these antibodies to PC 12 cells leads to the inhibition of the neurotoxic effects of beta-amyloid. Some of the mAbs raised against soluble beta-peptide (1-28) have been found to prevent in vitro fibrillar aggregation of beta-amyloid peptide. These experimental data suggest that site-directed mAbs interfere with the aggregation of beta-amyloid and trigger reversal to its nontoxic, normal components. The above findings give hints on how to convert in vivo senile plaques into nontoxic, diffuse components and may have therapeutic interest for those studying Alzheimer disease and other human diseases related to amyloidogenic properties of physiological peptides and proteins.

Alzheimer Disease↗
PubMed2002

Amyloid fibril formation by pentapeptide and tetrapeptide fragments of human calcitonin.

The process of amyloid fibril formation by the human calcitonin hormone is associated with medullary thyroid carcinoma. Based on the effect of pH on the fibrillization of human calcitonin, the analysis of conformationally constrained analogues of the hormone, and our suggestion regarding the role of aromatic residues in the process of amyloid fibril formation, we studied the ability of a short aromatic charged peptide fragment of calcitonin (NH(2)-DFNKF-COOH) to form amyloid fibrils. Here, using structural and biophysical analysis, we clearly demonstrate the ability of this short peptide to form well ordered amyloid fibrils. A shorter truncated tetrapeptide, NH(2)-DFNK-COOH, also formed fibrils albeit less ordered than those formed by the pentapeptide. We could not detect amyloid fibril formation by the NH(2)-FNKF-COOH tetrapeptide, the NH(2)-DFN-COOH tripeptide, or the NH(2)-DANKA-COOH phenylalanine to the alanine analogue of the pentapeptide. The formation of amyloid fibrils by rather hydrophilic peptides is quite striking, because it was speculated that hydrophobic interactions might play a key role in amyloid formation. This is the first reported case of fibril formation by a peptide as short as a tetrapeptide and one of very few cases of amyloid formation by pentapeptides. Because the aromatic nature seems to be the only common property of the various very short amyloid-forming peptides, it further supports our hypothesis on the role of aromatic interactions in the process of amyloid fibril formation.

Amino Acid Sequence↗
PubMed2005

Quantitative high-resolution microradiographic imaging of amyloid deposits in a novel murine model of AA amyloidosis.

The mouse model of experimentally induced systemic AA amyloidosis is long established, well validated, and closely analogous to the human form of this disease. However, the induction of amyloid by experimental inflammation is unpredictable, inconsistent, and difficult to modulate. We have previously shown that murine AA amyloid deposits can be imaged using iodine-123 labeled SAP scintigraphy and report here substantial refinements in both the imaging technology and the mouse model itself. In this regard, we have generated a novel prototype of AA amyloid in which mice expressing the human interleukin 6 gene, when given amyloid enhancing factor, develop extensive and progressive systemic AA deposition without an inflammatory stimulus, i.e., a transgenic rapidly inducible amyloid disease (TRIAD) mouse. Additionally, we have constructed high-resolution micro single photon emission computed tomography (SPECT)/computed tomography (CT) instrumentation that provides images revealing the precise anatomic location of amyloid deposits labeled by radioiodinated serum amyloid P component (SAP). Based on reconstructed microSPECT/CT images, as well as autoradiographic, isotope biodistribution, and quantitative histochemical analyses, the (125)I-labeled SAP tracer bound specifically to hepatic and splenic amyloid in the TRIAD animals. The ability to discern radiographically the extent of amyloid burden in the TRIAD model provides a unique opportunity to evaluate the therapeutic efficacy of pharmacologic compounds designed to inhibit fibril formation or effect amyloid resolution.

Amyloid↗
PubMed1997

Monomeric and dimeric beta 2-microglobulin may be extracted from amyloid deposits in vitro.

BACKGROUND: There is a controversy as to whether beta 2-microglobulin (beta 2M amyloid deposits may be degraded resulting in regression and cure of amyloidosis. We have recently reported a long-term clinical study involving transplanted patients suggesting that there is no resorption of amyloid deposits in vivo, even after correction of the primary cause of amyloidosis. To progress in the study of the solubility of amyloid fibrils we performed an in vitro study with the intent to remove protein constituents from amyloid fibrils and amyloid deposits. METHODS: Amyloid fibrils were prepurified from three amyloid deposits surgically obtained from carpal tunnel. They were incubated for 2 h with a phosphate-buffered saline (PBS) solution containing trypsin, collagenase, kallikrein, the three of them, or PBS alone. The experiments were repeated in the presence of the antiprotease alpha 2 macroglobulin (alpha 2M). RESULTS: Several bands were observed when the supernatants were run through SDS-PAGE. Western blotting identified in these bands the presence of alpha 2M, light chains of immunoglobulins and beta 2M in mono- and dimeric form. The same proteins were solubilized with PBS alone. Equivalent results were obtained with crude amyloid deposits; however, beta 2M presented almost exclusively in monomeric form. CONCLUSIONS: These results show that the protein constituents may be recovered from amyloid fibrils in vitro. They also show that even the more insoluble beta 2M dimers are resuspended by the action of PBS, with no need for proteases to cleave their attachment to the amyloid deposits.

Amyloid↗
PubMed1996

Evidence of blood-brain barrier permeability/leakage for circulating human Alzheimer's beta-amyloid-(1-42)-peptide.

Brains from patients with Alzheimer's disease contain amyloid plaques which are composed of beta-amyloid peptide and are considered to play a causal role in the neuropathology of this disease. The origin of beta-amyloid peptide in brain parenchyma and vessels of Alzheimer's disease patients is not known. This study examined the permeability of the blood-brain barrier to beta-amyloid peptide in rats subjected to single or repeated episodes of global cerebral ischaemia followed by i.v. injections of human synthetic beta-amyloid-(1-42)-peptide. Rats receiving beta-amyloid peptide after ischaemia demonstrated multifocal and widespread accumulation of beta-amyloid peptide in hippocampus, cerebral cortex and occasionally in white matter. beta-Amyloid peptide penetration involved arterioles, veins and venules. Neuronal, glial and pericyte bodies were observed filled with beta-amyloid peptide. Direct evidence that soluble human beta-amyloid-(1-42)-peptide crosses the blood-brain barrier and enters the brain from the circulation is thus provided for the first time.

Amyloid beta-Peptides↗
PubMed2002

Subepithelial amyloid deposits in congenital hereditary endothelial dystrophy: a histopathologic study of five cases.

PURPOSE: To report the clinical, histologic, ultrastructural, and immunohistochemical features of congenital hereditary endothelial dystrophy (CHED) associated with subepithelial amyloid deposits. METHODS: The clinical features of seven patients and histologic characteristics of eight corneal buttons were evaluated. The corneal specimens included five cases with histologic features of CHED associated with subepithelial amyloid. The remaining three corneal buttons of CHED without amyloid were obtained from the fellow eye of an affected patient and from siblings of two affected patients. Light microscopic studies were performed on sections stained with hematoxylin and eosin, periodic acid Schiff stain, and Congo red stain with and without permanganate bleach. Immunohistochemistry with an antibody to the amyloid AA protein and lambda and kappa light chains was done on all specimens. Electron microscopy was performed on three corneal specimens. The cases were followed for 1-9 years. RESULTS: The notable clinical findings included decreased vision, history of parental consanguinity (4/7 cases), and affected siblings (5/7 cases). Examination revealed nystagmus (5/7 cases) and bilateral ground-glass corneas in all patients. In addition, central subepithelial whitish opacities were noted in patients with CHED and amyloid. Three patients had associated congenital glaucoma. The patients underwent penetrating keratoplasty at a mean age of 10 years. Histologically, five corneal buttons of CHED revealed varying degrees of subepithelial amyloid deposits associated with a subepithelial fibrous pannus. Immunohistochemically, the deposits were nonreactive to anti-amyloid A antibody but were immunoreactive with an antibody to lambda light chains in two cases. Electron microscopy confirmed the presence of subepithelial amyloid. Thickening of Descemet's membrane and attenuation of corneal endothelial cells, noted in all cases, was consistent with features of CHED. The corneal buttons from the fellow eye and the siblings showed histologic features of CHED, with a subepithelial fibrous pannus without amyloid deposits. Spheroidal degeneration was noted in two corneal specimens. To date, no recurrence of the amyloid deposits has been seen in the grafts. CONCLUSIONS: This study demonstrates that subepithelial amyloidosis may be rarely associated with a recessive form of congenital hereditary endothelial dystrophy. The clinical, histologic, and immunohistochemical features suggest a secondary form of amyloidosis.

Adolescent↗
PubMed1990

Distribution of the protease inhibitor alpha 1-antichymotrypsin in cerebral and systemic amyloid.

We performed immunocytochemical staining to study the distribution of serum protease inhibitors in cerebral and systemic amyloid deposits. In beta-protein amyloid deposits in Alzheimer's disease, Down's syndrome, age-related cerebral amyloidosis, sporadic cerebral amyloid angiopathy and hereditary cerebral hemorrhage with amyloidosis of Dutch origin, antibody to alpha 1-antichymotrypsin (ACT) stains senile plaques and vascular deposits. Immature plaques or preamyloid deposits, identified by their positive staining for beta-protein and negative staining for Congo red, which represents the earliest recognizable stages of amyloid deposition, are also labeled. We did not detect ACT in other chemically different forms of cerebral and systemic amyloid. None of the other inhibitors in this study, i.e. antithrombin III and alpha 2-macroglobulin, was detected in the amyloid deposits. Neurons and glial cells throughout the central nervous system in normal and amyloid-containing brains also bind ACT antibody. The results emphasize the close association of ACT with one type of cerebral amyloid (beta-amyloid diseases) as well as the failure to detect such an association in other chemically different forms of cerebral and systemic amyloids.

Amyloid↗
PubMed1988

Differential staining of skin-limited amyloid and colloid bodies with immunofluorescence after pretreatments.

We examined whether immunoglobulin (Ig) and complement (C) components of amyloid and colloid bodies were inherent parts of these substances or were present due to nonspecific absorption only. In direct immunofluorescence (IF) studies without pretreatment, skin-limited and systemic amyloid and colloid bodies in all cases showed positive staining for Ig or C. When these sections were pretreated with 0.1 M glycine buffer (pH 7.2) or 0.05% Tween-20 solution, Ig and C in skin-limited amyloid deposits were negative or weakly positive. In contrast, positive fluorescence of colloid bodies and systemic amyloid masses was not influenced by pretreatment. Existence of amyloid masses before and after pretreatment were confirmed by Thioflavin-T and Dylon stains. In addition, pretreatment did not alter disulfide bonds by DACM staining or the reactivities of amyloid with monoclonal antikeratin antibody EKH4. These results suggest that skin-limited amyloid can be differentiated from systemic amyloid or colloid bodies by these methods. We can infer from the present studies that most of the Ig and C in skin-limited amyloid masses are a result of nonspecific absorption due to penetration of serum, which is different from Ig in systemic amyloid and colloid bodies in as much as in these conditions immunobinding is specific.

Amyloid↗
PubMed1992

Multinodular deposition of AA-type amyloid localized in the adrenal glands of an old man.

Multinodular amyloid deposits localized in non-neoplastic adrenal glands were found incidentally at autopsy in an 83-year-old Japanese man. Clinically, the patient lacked evident deficiency of adrenal hormones. The nodules of the stromal amyloid deposits were scattered in the adrenal cortex, where the parenchymal cells were compressed and atrophic. The deposits were confirmed to be amyloid by Congo red staining and polarization microscopy. Amyloid fibrils were also demonstrated in the deposits by electron microscopy. The amyloid deposits were permanganate-sensitive and showed immunohistochemical staining for serum amyloid P component and serum amyloid A protein (SAA), implying that they were AA amyloid. There have been no reports describing localized amyloid deposits of the AA type in non-neoplastic adrenal glands. The pathogenesis and clinical significance of the amyloid deposition in the present case remain only speculative.

Adrenal Glands↗
PubMed2000

Apolipoprotein E and Alzheimer's disease. A role in amyloid catabolism.

It has been shown over the past few years that apolipoprotein E (apoE) plays a central role in the brain response to injury and neurodegeneration in mammalian species. The coordinated expression of apoE and its different receptors, the so-called LDL receptor family, appears to regulate the transport of cholesterol and phospholipids during the early and middle phases of the reinnervation in the adult mammalian brain. As neurons undergo dendritic remodelling and synaptogenesis using cholesterol internalization through the apoE/LDL receptor pathway, they progressively shut down 3,3-hydroxymethylglutaryl-Coenzyme A (HMG CoA) reductase activity, the rate-limiting enzyme in the synthesis of cholesterol. These results suggest that cholesterol delivery and synthesis in the brain are tightly regulated through an apoE-dependent mechanism. The discovery that the apolipoprotein e4 allele is strongly linked to both sporadic and familial late-onset Alzheimer's disease (AD) has raised the possibility that a dysfunction of lipid transport could explain the poor compensatory synaptogenesis reported by several independent research groups in the brain of AD subjects. Recently, it has been shown that alterations of cholesterol homeostasis in the brain by exogenous administration of dietary cholesterol, or through inhibition of cholesterol synthesis, markedly affect beta amyloid production (1-40 and 1-42) and deposition and significantly impair amyloid precursor protein (APP) metabolism. In vivo, it has been shown that breeding of APP-overexpressing mice with apoE knockout mice completely abolishes amyloid plaque deposition in the brain of hybrid animals, without affecting beta amyloid steady state levels. Conversely, introduction of the human apoE3 and apoE4 genes in APP-overexpressing mice drastically reduced beta amyloid deposition in the brain of hybrid mice, confirming the proposed biological role of apoE in the clearance of extracellular beta amyloid. These results indicate that lipid homeostasis is controlled in large part by the apoE lipoprotein transport system in the extracellular space, whereas alterations in intracellular lipid homeostasis markedly affect APP processing, beta amyloid production and plaque formation in vivo. The convergence of the so-called amyloid cascade hypothesis (Hardy et al., 1992) and of the apoE/lipid recycling cascade model (Poirier, 1994) is consistent with the notion that alterations in lipid homeostasis could serve as the common denominator for apoE and beta amyloid dysfunctions in Alzheimer's disease. It is also interesting to note that lipid homeostasis is also a central feature of one of the most important neurotransmitter systems in the brain: the cholinergic system. This system is unique in the CNS since it relies heavily on lipid bioavailability to locally synthesize acetylcholine. It is thus quite tempting to propose that two of the most common neuropathologic landmarks of AD--namely, cholinergic dysfunction and amyloid deposition--may in fact depend on the integrity of local lipid homeostatic processes, which in turn are strongly dependent upon proper lipid delivery by the apoE transport system.

Alzheimer Disease↗
PubMed1991

Deposits of amyloid beta protein in the central nervous system of transgenic mice.

Alzheimer's disease is characterized by widespread deposition of amyloid in the central nervous system. The 4-kilodalton amyloid beta protein is derived from a larger amyloid precursor protein and forms amyloid deposits in the brain by an unknown pathological mechanism. Except for aged nonhuman primates, there is no animal model for Alzheimer's disease. Transgenic mice expressing amyloid beta protein in the brain could provide such a model. To investigate this possibility, the 4-kilodalton human amyloid beta protein was expressed under the control of the promoter of the human amyloid precursor protein in two lines of transgenic mice. Amyloid beta protein accumulated in the dendrites of some but not all hippocampal neurons in 1-year-old transgenic mice. Aggregates of the amyloid beta protein formed amyloid-like fibrils that are similar in appearance to those in the brains of patients with Alzheimer's disease.

Alzheimer Disease↗