Studies on the first described Alzheimer's disease amyloid β mutant, the Dutch variant

Department of Pharmacology, New York University School of Medicine, New York, New York, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 02/2006; 9(3 Suppl):329-39.
Source: PubMed


Amyloid protein deposited in cerebral vessel walls and diffuse plaques of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), is similar to the 40-42 residues amyloid beta (Abeta) in vessel walls and senile plaques in brains of patients with Alzheimer's disease (AD), Down's syndrome, and familial and sporadic cerebral amyloid angiopathy (CAA). In 1990 we sequenced the amyloid beta-protein precursor (AbetaPP) gene from HCHWA-D patients revealing a single mutation that results in an amino acid substitution, Abeta E22Q. Subsequent identification of additional mutations in the AbetaPP gene in familial AD (FAD) pedigrees revealed that whereas substitutions in the middle of Abeta, residues Abeta21-23, are predominantly vasculotropic, those found amino- or carboxyl-terminal to the Abeta sequence within AbetaPP enhance amyloid parenchymal plaque deposition. Studies of transfected cells showed that substitutions amino- or carboxyl-terminal to Abeta lead to either greater Abeta production or to enhanced secretion of the more hydrophobic thus more fibrillogenic Abeta1-42. Substitutions in the center of Abeta facilitate rapid aggregation and fibrillization, slower clearance across the blood-brain barrier and perivascular drainage to the systemic circulation, possibly higher resistance to proteolysis, and enhanced toxicity towards endothelial and smooth muscle cells. However, most AD patients have no genetic defects in AbetaPP, indicating that other factors may alter Abeta production, conformation, and/or clearance initiating the disease process.

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Available from: Frances Prelli, Jul 01, 2015
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    • "Milestones in A-AD research have been the demonstration that: i) the characteristic senile plaques in AD brains consist of A aggregates [2]; ii) amyloid-protein precursor (APP) is located on chromosome 21 (21q21.2-3) [3] [4], the same chromosome is involved in Down syndrome , which is characterized by A deposition and AD-like neurodegeneration [5]; and iii) APP genetic mutations are involved in familial AD [6] [7] [8] [9] [10]. APP and its processing have been intensively investigated. "
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    ABSTRACT: Amyloid-β peptide (Aβ) is considered a key protein in the pathogenesis of Alzheimer's disease (AD) because of its neurotoxicity and capacity to form characteristic insoluble deposits known as senile plaques. Aβ derives from amyloid-β protein precursor (AβPP), whose proteolytic processing generates several fragments including Aβ peptides of various lengths. The normal function of AβPP and its fragments remains poorly understood. While some fragments has been suggested to have a function in normal physiological cellular processes, Aβ has been widely considered as a "garbage" fragment that becomes toxic when it accumulates in the brain, resulting in impaired synaptic function and memory. Aβ is produced and released physiologically in the healthy brain during neuronal activity. In the last 10 years, we have been investigating whether Aβ plays a physiological role in the brain. We first demonstrated that picomolar concentrations of a human Aβ42 preparation enhanced synaptic plasticity and memory in mice. Next, we investigated the role of endogenous Aβ in healthy murine brains and found that treatment with a specific antirodent Aβ antibody and an siRNA against murine AβPP impaired synaptic plasticity and memory. The concurrent addition of human Aβ42 rescued these deficits, suggesting that in the healthy brain, physiological Aβ concentrations are necessary for normal synaptic plasticity and memory to occur. Furthermore, the effect of both exogenous and endogenous Aβ was seen to be mediated by modulation of neurotransmitter release and α7-nicotinic receptors. These findings need to be taken into consideration when designing novel therapeutic strategies for AD.
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    • "Similarly, transgenic mice expressing the E22Q mutation showed behavioural deficits in advance of amyloid deposition in either the vasculature or parenchyma (Kumar-Singh et al., 2000). Together these results suggest that preclinical cognitive problems may be present before significant angiopathy, but that frank cerebral amyloid angiopathy may be required for the fulminant expression of the disease (Maat-Schieman et al., 2005; Levy et al., 2006; Xu et al., 2007). "
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    ABSTRACT: Long before the onset of clinical Alzheimer's disease non-fibrillar, soluble assembly states of amyloid-beta (Abeta) peptides are believed to cause cognitive problems by disrupting synaptic function in the absence of significant neurodegeneration. Since many of the risk factors for Alzheimer's disease are vascular, impairment of cerebral blood flow by soluble Abeta has been proposed to be critical in triggering these early changes. However, it is not known if soluble Abeta can affect cerebrovascular function at the concentrations required to cause inhibition of synaptic plasticity mechanisms believed to underlie the early cognitive deficits of Alzheimer's disease. Here we developed a new method to simultaneously assess the ability of soluble Abeta to impair plasticity at synapses and to affect resting and activity-dependent local blood flow in the rat hippocampus in vivo. Intracerebroventricular injection of soluble synthetic Abeta(40) dimers rapidly inhibited plasticity of excitatory synaptic transmission at doses (10-42 pmol) comparable to natural Abeta, but failed to affect vascular function measured using laser-Doppler flowmetry (LDF). Like wild-type Abeta(40), the more vasculotropic Abeta produced by people with familial hemorrhagic stroke of the Dutch type (Abeta(40)E22Q), impaired hippocampal plasticity without causing a significant change in local blood flow. Furthermore, neither resting nor activation-evoked hippocampal perfusion was affected by soluble Abeta(42), even at a concentration that markedly (25%) reduced baseline synaptic transmission. These findings demonstrate that the putative synaptotoxic soluble Abeta species of early Alzheimer's disease cause synaptic dysfunction in the absence of detectible changes in local blood flow. This strongly indicates that early cognitive deficits can be caused by soluble Abeta independently of deleterious effects on cerebrovascular dynamics.
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    ABSTRACT: Ektodomänenspaltung und Intramembranproteolyse des Amyloiden Vorläufer Proteins (APP) durch Alpha-, Beta- und gamma-Sekretase sind in die Pathogenese der Alzheimer Erkrankung (AD) involviert. Eine vermehrte proteolytische Prozessierung und Sekretion eines anderen Membranproteins, des Typ II Interleukin-1 Rezeptors (IL-1R2) wurde mit der Pathogenese der Alzheimer Erkrankung in Verbindung gebracht. IL-1R2 ist ein Abfangrezeptor, welcher vermutlich in der Lage ist, die schädlichen Effekte von Interleukin-1 im Gehirn zu begrenzen. Bis jetzt ist die proteolytische Prozessierung von IL-1R2 nur wenig verstanden. In dieser Arbeit wird gezeigt, dass IL-1R2 ähnlich wie auch APP prozessiert wird. In humanen embryonalen Nierenzellen (HEK293) exprimiertes IL-1R2 unterläuft zuerst eine Spaltung der Ektodomäne durch eine Metalloprotease, was zur Freisetzung der Ektodomäne und einem in der Membran verbleibenden C-terminalen Fragment führt. Dieses Fragment wird durch Intramembranproteolyse des Gamma-Sekretase-Komplexes in eine intrazelluläre Domäne (ICD) gespalten. Die Intramembranproteolyse von IL-1R2 konnte durch einen hochspezifischen Gammasekretase-Inhibitor gehemmt werden und fehlte in Gamma-Sekretase-defizienten embryonalen Mausfibroblasten. Überraschenderweise erhöhen die Beta-Sekretase BACE1 und ihr Homolog BACE2 die Sekretion von IL-1R2, welche zu ähnlich großen C-terminalen Fragmenten wie auch bei der Alpha-Spaltung von IL-1R2 führen. Dies könnte bedeuten, dass beide Proteasen als alternative Alpha-Sekretasen agieren könnten. Darüber hinaus werden zahlreiche andere Membranproteine, die in dieser Arbeit untersucht wurden, nicht durch BACE1 und BACE2 geschnitten, was zeigt, dass beide Proteasen nicht am generellen Membranproteinumsatz beteiligt sind. Diese Arbeit zeigt, dass Il-1R2 und APP eine ähnliche proteolytische Prozessierung durchlaufen. Dies könnte somit eine Erklärung für die erhöhte Sekretion von IL-1R2 im Rahmen der Alzheimer Erkrankung sein.
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