Alzheimer's Disease Amyloid β Peptide 25-35 Is Localized in the Membrane Hydrocarbon Core: X-Ray Diffraction Analysis

Mason, R. Preston; Estermyer, Janet D.; Kelly, Jeremiah F.; Mason, Pamela E.

doi:10.1006/bbrc.1996.0699

Cited by 101 publications

(89 citation statements)

References 14 publications

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“…However the monomeric form may pass through the membrane so the state of aggregation only has a positive influence on this passage, rather than the entire /3A fibril interacting with the membrane and triggering the biological response. According to this hypothesis, x-ray diffraction analysis indicates that /325-35 in monomeric form has a strong hydrophobic interaction with the membrane hydrocarbon core (Mason et al, 1996). Furthermore, the recent identification of RAGE ("receptors for advanced glycation end products") as a receptor that partially mediates the effects of/3A peptides (/31-42 and /325-35) on neurons and microglia did not clarify whether neurotoxicity is activated by the monomer or aggregated form (Yan et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Amidation of β‐Amyloid Peptide Strongly Reduced the Amyloidogenic Activity Without Alteration of the Neurotoxicity

Forloni

Lucca

Angeretti

et al. 1997

Journal of Neurochemistry

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/3-Amyloid accumulates in cerebral deposits in Alzheimer's disease, so to test the correlation between the neurotoxic and fibrillogenic capacity of /3-amyloid, we synthesized a peptide homologous to fragment 25-35 of /3-amyloid (/325-35) and amidated at the C-terminus (/325-35-NH 2). As the amidation strongly reduced the amyloidogenic capacity of /325-35, we compared its neurotoxic activity in the amidated (/325-35-NH2) and nonamidated forms. The viability of primary cultures from fetal rat hippocampus was reduced in a dose-related manner (10-100~sM)similarly by /325-35 and /325-35-NH2, whereas a scrambled peptide, amidated or nonamidated, did not alter the neuronal viability. The neurotoxic activity of /325-35-NH2 is mediated by apoptosis as demonstrated by morphological and biochemical investigations. Electron microscopy examination of culture media with /325-35 or /325-35-NH2 incubated with neuronal cells for 7 days confirmed the high level of fibrillogenic activity of /325-35 and the almost total absence of fibrils in the solution with /325-35-NH2. Furthermore, staining with thioflavine S was used to identify amyloid fibrils, and only the cultures exposed to /325-35 exhibited intense staining associated with neuronal membranes. These data indicate that the neurotoxic activity of the /3-amyloid fragment is independent of the aggregated state of the peptide.

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Section: Discussionmentioning

confidence: 99%

Amidation of β‐Amyloid Peptide Strongly Reduced the Amyloidogenic Activity Without Alteration of the Neurotoxicity

Forloni

Lucca

Angeretti

et al. 1997

Journal of Neurochemistry

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“…A recent study from Cotman and co-workers (12) showed that A␤ neurotoxicity is independent of stereoisomerspecific ligand-receptor interaction because both all-D-and all-L-stereoisomers of A␤ [25][26][27][28][29][30][31][32][33][34][35] and A␤ had similar neurotoxic activity. This finding suggests that A␤ modulates membrane function by a nonreceptor-mediated mechanism, potentially as a result of altering the physico-chemical properties of membrane constituents, including lipids and proteins (13)(14)(15)(16). Indeed, previous membrane equilibrium binding experiments have demonstrated that the A␤ [25][26][27][28][29][30][31][32][33][34][35] fragment is highly lipophilic (K P Ͼ 10 2 ); the peptide intercalates deep into the membrane bilayer hydrocarbon core, as determined by small angle x-ray diffraction approaches (15).…”

mentioning

confidence: 99%

“…This finding suggests that A␤ modulates membrane function by a nonreceptor-mediated mechanism, potentially as a result of altering the physico-chemical properties of membrane constituents, including lipids and proteins (13)(14)(15)(16). Indeed, previous membrane equilibrium binding experiments have demonstrated that the A␤ [25][26][27][28][29][30][31][32][33][34][35] fragment is highly lipophilic (K P Ͼ 10 2 ); the peptide intercalates deep into the membrane bilayer hydrocarbon core, as determined by small angle x-ray diffraction approaches (15). In addition, aggregated A␤ has strong electrostatic interactions with the surface of model membranes that appear to mediate its neurotoxicity (17).…”

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confidence: 99%

Distribution and Fluidizing Action of Soluble and Aggregated Amyloid β-Peptide in Rat Synaptic Plasma Membranes

Mason

Jacob

Walter

et al. 1999

Journal of Biological Chemistry

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110

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The effects of soluble and aggregated amyloid ␤-peptide (A␤) on cortical synaptic plasma membrane (SPM) structure were examined using small angle x-ray diffraction and fluorescence spectroscopy approaches. Electron density profiles generated from the x-ray diffraction data demonstrated that soluble and aggregated A␤ 1-40 peptides associated with distinct regions of the SPM. The width of the SPM samples, including surface hydration, was 84 Å at 10°C. Following addition of soluble A␤ 1-40 , there was a broad increase in electron density in the SPM hydrocarbon core ؎0 -15 Å from the membrane center, and a reduction in hydrocarbon core width by 6 Å. By contrast, aggregated A␤ 1-40 contributed electron density to the phospholipid headgroup/hydrated surface of the SPM ؎24 -37 Å from the membrane center, concomitant with an increase in molecular volume in the hydrocarbon core. The SPM interactions observed for A␤ 1-40 were reproduced in a brain lipid membrane system. In contrast to A␤ 1-40 , aggregated A␤ 1-42 intercalated into the lipid bilayer hydrocarbon core ؎0 -12 Å from the membrane center. Fluorescence experiments showed that both soluble and aggregated A␤ 1-40 significantly increased SPM bulk and protein annular fluidity. Physico-chemical interactions of A␤ with the neuronal membrane may contribute to mechanisms of neurotoxicity, independent of specific receptor binding. Alzheimer's disease (AD)1 is a progressive neurodegenerative disorder characterized by the accumulation of neuritic plaques composed of amyloid ␤-peptide (A␤) variants, extracellular matrix components, and apolipoproteins (1, 2). A␤ is an amphipathic, 39 -42-residue peptide that is derived by proteolytic cleavage of the transmembrane glycoprotein, the amyloid precursor protein; the A␤ domain is composed of 28 extracellular and 12-14 transmembrane amino acid residues of amyloid precursor protein (3). An increase in the production and abnormal accumulation of A␤ in the brain has been implicated in the etiology of AD. Several studies have shown that A␤ analogs can directly disrupt neuronal function, contributing to cell death associated with the development of AD (4 -8).It has been postulated that the biological activity of A␤ is related to its ability to form insoluble aggregates in solution (9 -11), although the cellular mechanism of action is not well understood. A recent study from Cotman and co-workers (12) showed that A␤ neurotoxicity is independent of stereoisomerspecific ligand-receptor interaction because both all-D-and all-L-stereoisomers of A␤ [25][26][27][28][29][30][31][32][33][34][35] and A␤ 1-40 had similar neurotoxic activity. This finding suggests that A␤ modulates membrane function by a nonreceptor-mediated mechanism, potentially as a result of altering the physico-chemical properties of membrane constituents, including lipids and proteins (13-16). Indeed, previous membrane equilibrium binding experiments have demonstrated that the A␤ 25-35 fragment is highly lipophilic (K P Ͼ 10 2 ); the peptide intercalates deep into the membra...

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“…The interaction of AßP (25-35) with 1-palmitoyl-2-oleoyl phosphatidylcholine was examined by Xray diffraction analysis. The authors suggested that lysine-28 may be at the hydrocarbon-water interface and the seven hydrophobic amino acids positioned in the hydrocarbon core as an a helix [16]. The intercalation of AßP (25-35) may provoke a restricted or generalized membrane perturbation.…”

Section: Discussionmentioning

confidence: 99%

“…However, the stimulation of PLC must have an additional factor. The hydrophilic amino acids at the N terminal position of AßP (25-35) are thought to be unrestricted [15] but may interact with phosphate headgroups of the membrane phospholipids [16]. This additional interaction seems necessary for the observed PLC activation in addition to the hydrophobic interactions with the membrane core.…”

Section: Discussionmentioning

confidence: 99%

Activation of LA‐N‐2 cell phospholipases by single alanine substitution analogs of amyloid β peptide (25–35)

et al. 1997

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USA. AßP (1-40) was purchased from Bachern, Torrance, CA, USA. The single alanine substituted AßP (25-35) analogs were synthesized as described [8] and the sequences are shown in Fig. 1. AßP (28-34) and AßP (1-42) were synthesized in a similar manner. The peptides were dissolved in water to provide stock solutions of 10 mg/ ml. The human neuroblastoma cell line LA-N-2 was obtained from Dr. Robert Seeger of the University of California, Los Angeles, CA, USA, and maintained as previously described [11].

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Alzheimer's Disease Amyloid β Peptide 25-35 Is Localized in the Membrane Hydrocarbon Core: X-Ray Diffraction Analysis

Cited by 101 publications

References 14 publications

Amidation of β‐Amyloid Peptide Strongly Reduced the Amyloidogenic Activity Without Alteration of the Neurotoxicity

Amidation of β‐Amyloid Peptide Strongly Reduced the Amyloidogenic Activity Without Alteration of the Neurotoxicity

Distribution and Fluidizing Action of Soluble and Aggregated Amyloid β-Peptide in Rat Synaptic Plasma Membranes

Activation of LA‐N‐2 cell phospholipases by single alanine substitution analogs of amyloid β peptide (25–35)

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