The beta-amyloid domain is essential for axonal sorting of amyloid precursor protein.

Tienari, PJ; Strooper, Bart De; Ikonen, Elina; Simons, Mikael; Weidemann, Andreas; Czech, Christian; Hartmann, Tobias; Ida, Nobuo; Multhaup, Gerd; Masters, Colin L.; Leuven, Freddy Van; Beyreuther, Konrad; Dotti, Carlos G.

doi:10.1002/j.1460-2075.1996.tb00907.x

Cited by 129 publications

(116 citation statements)

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“…We investigated whether cholesterol depletion would affect secretion of A␤40 and A␤42 in neurons. We expressed the human APP gene in primary rat hippocampal neurons by infection with SFV encoding the human APP (SFV-APP) (23,(30)(31)(32). Cholesterol was depleted from hippocampal neurons by two different strategies.…”

Section: Resultsmentioning

confidence: 99%

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Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo

Faßbender

Simons

Bergmann

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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1,039

724

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Recent epidemiological studies show a strong reduction in the incidence of Alzheimer's disease in patients treated with cholesterol-lowering statins. Moreover, elevated A␤42 levels and the 4 allele of the lipid-carrier apolipoprotein E are regarded as risk factors for sporadic and familial Alzheimer's disease. Here we demonstrate that the widely used cholesterol-lowering drugs simvastatin and lovastatin reduce intracellular and extracellular levels of A␤42 and A␤40 peptides in primary cultures of hippocampal neurons and mixed cortical neurons. Likewise, guinea pigs treated with high doses of simvastatin showed a strong and reversible reduction of cerebral A␤42 and A␤40 levels in the cerebrospinal fluid and brain homogenate. These results suggest that lipids are playing an important role in the development of Alzheimer's disease. Lowered levels of A␤42 may provide the mechanism for the observed reduced incidence of dementia in statin-treated patients and may open up avenues for therapeutic interventions.A part from age, environmental factors have only slight influence on the incidence of Alzheimer's disease (AD). Very recently, two independent reports showed a strong decrease in the incidence of AD and dementia for patients that were treated with statins (1, 2). Both studies were retrospective, and statins were not given in any relation to dementia. Usually statins are prescribed for treatment of elevated serum cholesterol levels in patients. They reduce cholesterol levels by inhibiting the bottleneck enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. They are widely used drugs, well characterized and considered to be very safe for long-time treatment, and approved for use in elderly patients (3, 4).The 4 allele of the apolipoprotein E (apoE) is the major genetic risk factor for AD (5). Several lines of evidence indicate that apoE 4 and statins have a related influence on AD. The normal cellular function of apoE is uptake and delivery of lipids. The isoform apoE 4 correlates with an increased risk for atherosclerosis (6) and amyloid plaque formation (7). Moreover, elevated cholesterol uptake increases amyloid plaque formation or amyloid deposition (8,9). This correlation may be extended to A␤ production, since cellular cholesterol levels affect neuronal A␤ production in vitro (10). Initially, A␤ has been a focus of AD research, because it was found to be the major constituent of the amyloid plaque. It is unknown whether the amyloid plaque is actively involved in the neurodegenerative process in AD or instead is a consequence of the disease process. More recently, however, A␤ has been a focus of AD research not because of it presence in the amyloid plaque, but because an overproduction of a minor A␤ isoform, A␤42, is linked to all identified inherited forms of AD (11-13).A␤ is produced during normal cellular processing of the Alzheimer amyloid precursor protein (APP) (14) by ␤-secretase and ␥-secretase (15). While the majority of all A␤ isoforms produced is A␤40, Ϸ10% of total A␤ ...

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Section: Resultsmentioning

confidence: 99%

“…Cholesterol is important for protein trafficking (44), and the A␤ domain in APP has been identified to be important for axonal transport of APP (32). Furthermore, A␤ is an apical targeted peptide in cholesterol-depleted MDCK cells (45).…”

Section: Discussionmentioning

confidence: 99%

Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo

Faßbender

Simons

Bergmann

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

1,039

724

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“…Without ␤-cleavage, ␥-cleavage of Sp-C111 produces a 5.5-kDa A␤-like peptide consisting of the A␤-domain and the first 12 amino acids preceding the A␤-domain. In this regard C111 resembles more the C99 construct that does not require ␤-secretase cleavage for ␥-secretase activation (56). Thus, the relevant A␤ generating secretases may act here independent of each other.…”

Section: Methodsmentioning

confidence: 99%

“…The SpeI site in the 3Ј-untranslated region of the APP cDNA was removed by Klenow polymerase and the resultant blunt ends were re-ligated prior to cloning into the expression vector pSFV1 (56). This was necessary as the pSFV1/APP have to be linearized from the SpeI site of pSFV1.…”

Section: Methodsmentioning

confidence: 99%

Independent Inhibition of Alzheimer Disease β- and γ-Secretase Cleavage by Lowered Cholesterol Levels

Grimm

Tomic

et al. 2008

Journal of Biological Chemistry

119

107

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The major molecular risk factor for Alzheimer disease so far identified is the amyloidogenic peptide A␤ 42 . In addition, growing evidence suggests a role of cholesterol in Alzheimer disease pathology and A␤ generation. However, the cellular mechanism of lipid-dependent A␤ production remains unclear. Here we describe that the two enzymatic activities responsible for A␤ production, ␤-secretase and ␥-secretase, are inhibited in parallel by cholesterol reduction. Importantly, our data indicate that cholesterol depletion within the cellular context inhibits both secretases additively and independently from each other. This is unexpected because the ␤-secretase ␤-site amyloid precursor protein cleaving enzyme and the presenilin-containing ␥-secretase complex are structurally different from each other, and these enzymes are apparently located in different subcellular compartments. The parallel and additive inhibition has obvious consequences for therapeutic research and may indicate an intrinsic cross-talk between Alzheimer disease-related amyloid precursor protein processing, amyloid precursor protein function, and lipid biology.A␤ peptides are the main proteinaceous component of Alzheimer disease amyloid plaques. A␤ is derived from posttranslational cleavage of the amyloid precursor protein (APP). Cleavage of APP by BACE I (1) at the N terminus of the A␤ sequence generates a C-terminal fragment (C99) that includes the entire A␤ sequence. In mouse cortical neurons BACE I is essential for APP ␤-cleavage (2). A second proteolytic activity termed ␥-secretase cleaves APP at the C-terminal end of the A␤ sequence, releasing A␤ 40 and A␤ 42 during normal cellular metabolism of APP (3, 4). A fraction of APP is processed by the ␣-secretase pathway in which APP is cleaved within the A␤ region thus precluding A␤ formation. However, neurons predominately use the ␤-secretory pathway at the expense of the ␣-secretory pathway to process APP (5). Moreover, neurons produce significant amounts of intracellular A␤ in vivo and in vitro (6 -8). A specific feature of ␥-secretase is that it is capable of cleaving APP only after a major part of the APP luminal domain is removed. Under normal circumstances it is therefore not possible to assay ␥-secretase activity directly.Analyses of APP-FAD mutations (9) as well as of PS-FAD mutations (10) have corroborated the assumption that a small increase in A␤ 42 levels causes AD (11). The subcellular activities of both ␤-and ␥-secretase have been extensively studied. Processing of APP to A␤ differs for different intracellular compartments (12) and depends among others on the interaction of membrane composition and the APP transmembrane domain (13). Variable amounts of ␤-secretase activity were found along the secretory pathway starting in the ER/intermediate compartment, post-Golgi vesicles, TGN, and endosomes (14, 15). In contrast, ␥-secretase activity was found to be prominent in the ER, TGN, and plasma membrane and to produce different A␤ isoforms in different compartments (reviewed by Hartmann (...

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“…Although APP, as a membrane receptor along with kinesin-1 microtubular motor protein, reaches an unprecedented fast and unidirectional axonal transportation, however, the exact nature of APP carriers into axons and dendrites is not fully recognized. Recently, it has been reported that the sorting signal of APP toward dendritic and axonal compartments seems to follow no specific pathways, 80 which implies the distinct behavior of neurons, compared to the other peripheral cells, for handling polarized trafficking of APP.…”

Section: ■ Intracellular Trafficking Of Appmentioning

confidence: 99%

Alzheimer’s Disease: Pathophysiology and Applications of Magnetic Nanoparticles as MRI Theranostic Agents

Amiri

Saeidi²,

Borhani³

et al. 2013

ACS Chem. Neurosci.

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Alzheimer's disease (AD) is the most common form of dementia. During the recent decade, nanotechnology has been widely considered, as a promising tool, for theranosis (diagnosis and therapy) of AD. Here we first discuss pathophysiology and characteristics of AD with a focus on the amyloid cascade hypothesis. Then magnetic nanoparticles (MNPs) and recent works on their applications in AD, focusing on the superparamagnetic iron oxide nanoparticles (SPIONs), are reviewed. Furthermore, the amyloid−nanoparticle interaction is highlighted, with the scope to be highly considered by the scientists aiming for diagnostics and/or treatment of AD employing nanoparticles. Furthermore, recent findings on the "ignored" parameters (e.g., effect of protein "corona" at the surface of nanoparticles on amyloid-β (Aβ) fibrillation process) are discussed. KEYWORDS: Magnetic resonance imaging, SPION, amyloid-β, nanomedicine, nanotechnology A lzheimer's disease (AD) is named after Alois Alzheimer, who described the first case in a 55 year old female patient (i.e., Auguste Deter) in 1906. The description of Auguste's pathology was featured by lifelong deteriorating memory, speaking, physical, and social abilities. After her death, the autopsy revealed uniform brain atrophy, atherosclerosis changes in larger cerebral vessels, neuronal loss, and numerous small foci perceivable even without staining distributed over the entire cortex. It took over 70 years to reveal that those foci consist of aggregates of extracellular loads of small peptides called amyloid-β (Aβ), that are considered today one of the hallmarks of the disease. 1 AD is characterized by progressive deterioration of cognitive function, most commonly of memory, that increasingly interferes with patients' daily activities leading to loss of independency (for details, see http://www.alz.org/downloads/ facts_figures_2012.pdf). To date, no precise treatments have been clinically proven to avoid or prevent the progression of AD. Several different pharmacological agents can only ameliorate or provide temporary alleviation of the symptoms. 2 In this review, we introduce clinical aspects and characteristics of AD with a focus on the amyloid cascade hypothesis. Magnetic nanoparticles (MNPs), as promising theranosis tools, are introduced, and recent reports on the potential applications of superparamagnetic iron oxide nanoparticles (SPIONs) in AD are summarized. It is worthwhile to note that the SPIONs are known as promising theranosis candidates for AD, due to their biocompatibility, unique magnetic properties and multifunctional application capability. 3,4 The amyloid−nanoparticle interaction is highlighted, with the scope to be highly considered by the scientific community aiming for diagnostics and/or treatment of AD employing nanoparticles. Moreover, recent findings on the "ignored" parameters (e.g., the effect of protein "corona" at the surface of nanoparticles on Aβ fibrillation process) are discussed.

show abstract

The beta-amyloid domain is essential for axonal sorting of amyloid precursor protein.

Cited by 129 publications

References 52 publications

Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo

Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo

Independent Inhibition of Alzheimer Disease β- and γ-Secretase Cleavage by Lowered Cholesterol Levels

Alzheimer’s Disease: Pathophysiology and Applications of Magnetic Nanoparticles as MRI Theranostic Agents

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