Amyloid β peptides act directly on single neurons

Simmons, Mark A.; Schneider, Carla R.

doi:10.1016/0304-3940(93)90519-q

Cited by 89 publications

(37 citation statements)

References 7 publications

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“…We suggest an important significance of this finding because a correlation appears to exist between biological effects of A␤ and its aggregation state (7)(8)(9)(10). Furthermore, it is believed that the fibrillar peptide itself represents the neurotoxic species.…”

Section: Ganglioside-containing Vesicles Promote A␤ Fibril Formation mentioning

confidence: 70%

Acceleration of Amyloid Fibril Formation by Specific Binding of Aβ-(1–40) Peptide to Ganglioside-containing Membrane Vesicles

Choo-Smith¹,

Garzon-Rodriguez²,

Glabe³

et al. 1997

Journal of Biological Chemistry

316

269

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The interaction of Alzheimer's A␤ peptide and its fluorescent analogue with membrane vesicles was studied by spectrofluorometry, Congo Red binding, and electron microscopy. The peptide binds selectively to the membranes containing gangliosides with a binding affinity ranging from 10 ؊6 to 10 ؊7 M depending on the type of ganglioside sugar moiety. This interaction appears to be ganglioside-specific as under our experimental conditions (neutral pH, physiologically relevant ionic strength), no A␤ binding was observed to gangliosidefree membranes containing zwitterionic or acidic phospholipids. Importantly, the addition of ganglioside-containing vesicles to the peptide solution dramatically accelerates the rate of fibril formation as compared with that of the peptide alone. The present results strongly suggest that the membrane-bound form of the peptide may act as a specific "template" (seed) that catalyzes the fibrillogenesis process in vivo.One of the histopathological hallmarks of Alzheimer's disease is the presence of insoluble amyloid deposits within the gray matter regions of the brain and the vascular walls of cerebral blood vessels (1). The principal component of these deposits is the ϳ4-kDa amyloid ␤ peptide (A␤), a product of proteolytic processing of a much larger amyloid precursor protein (2). While biological functions of A␤ are still poorly understood, rapidly accumulating evidence points to a causative (rather than merely consequential) role of the peptide in the pathogenesis of Alzheimer's disease. Such a causative link between A␤ and Alzheimer's disease is indicated by genetic studies which identified specific mutations in amyloid precursor protein (in close proximity to the amino or carboxyl terminus of A␤ or within the A␤ region) that are tightly linked to heritable forms of Alzheimer's disease (3-5). Further support is derived from in vitro studies which show that synthetic A␤ peptide is toxic to neuronal cells in culture (6 -9). However, despite recent important advances, the molecular mechanisms of A␤-induced neuronal cell death remain largely unknown.To understand the neurotoxic action of A␤, it is essential to identify specific cellular components that interact with the peptide and mediate a biological response of the affected cells. A likely primary target of A␤ is the neuronal plasma membrane. Indeed, a rapidly growing number of observations indicate that the peptide may alter important physical and biological properties of the membrane (10 -17). The mechanisms of A␤-membrane interactions remain, however, elusive. Whereas some investigators have proposed the involvement of specific proteinaceous receptors (18,19), other studies postulate models based on the interaction of A␤ with the lipid bilayer matrix of the plasma membrane (14, 15). Our present data show that A␤ binds with high affinity and selectivity to gangliosides. Furthermore, in the presence of ganglioside-containing membrane vesicles, there is a dramatic increase in the rate of fibril formation by the peptide. We postulate that t...

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Section: Ganglioside-containing Vesicles Promote A␤ Fibril Formation mentioning

confidence: 70%

Acceleration of Amyloid Fibril Formation by Specific Binding of Aβ-(1–40) Peptide to Ganglioside-containing Membrane Vesicles

Choo-Smith¹,

Garzon-Rodriguez²,

Glabe³

et al. 1997

Journal of Biological Chemistry

316

269

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“…It has been hypothesized that oligomeric Aβ, with its sharp morphology in contrast to monomeric Aβ, has the ability to permeabilize cellular membranes and lipid bilayers thereby entering organelles, such as the mitochondria [46,47]. Of note, early reports about the action of aggregated Aβ on membranes implicate increased membrane permeability elicited by fibrils [48,49]. These mechanisms might explain why aggregated Aβ preparations elicit effects on mitochondrial function, but not disaggregated Aβ.…”

Section: Discussionmentioning

confidence: 99%

Oligomeric and fibrillar species of β-amyloid (Aβ42) both impair mitochondrial function in P301L tau transgenic mice

et al. 2008

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We recently provided evidence for a mitochondrial dysfunction in P301L tau transgenic mice, a strain modeling the tau pathology of Alzheimer's disease (AD) and frontotemporal dementia (FTD). In addition to tau aggregates, the AD brain is further characterized by Aβ peptide-containing plaques. When we addressed the role of Aβ, this indicated a synergistic action of tau and Aβ pathology on the mitochondria. In the present study, we compared the toxicity of different Aβ42 conformations in light of recent studies suggesting that oligomeric rather than fibrillar Aβ might be the actual toxic species. Interestingly, both oligomeric and fibrillar, but not disaggregated (mainly monomeric) Aβ42 caused a decreased mitochondrial membrane potential in cortical brain cells obtained from FTD P301L tau transgenic mice. This was not observed with cerebellar preparations indicating selective vulnerability of cortical neurons. Furthermore, we found reductions in state 3 respiration, the respiratory control ratio, and uncoupled respiration when incubating P301L tau mitochondria either with oligomeric or fibrillar preparations of Aβ42. Finally, we found that aging specifically increased the sensitivity of mitochondria to oligomeric Aβ42 damage indicating that oligomeric and fibrillar Aβ42 are both toxic, but exert different degrees of toxicity.

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“…The A␤-induced increase in sEPSC frequency and amplitude confirms that A␤ caused an increase in glutamate release in cortical circuits. Previous studies have shown that A␤ induces Ca 2ϩ influx through VDCCs in cortical neurons and nerve cell lines (57,58), activates large, nonselective cation currents in sympathetic and cortical neurons (59,60), and inhibits several potassium currents in basal forebrain cholinergic neurons (61). Thus the A␤-induced alteration of cellular ionic activity through interaction with existing channels or de novo channel formation (62) might be one of the key mechanisms underlying the A␤ activation of neuronal excitability.…”

Section: A␤-induced Signaling In Corticalmentioning

confidence: 99%

Activation of Muscarinic Receptors Inhibits औ-Amyloid Peptide-induced Signaling in Cortical Slices

Zhong

Yan

2003

Journal of Biological Chemistry

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Deposition of fibrillar aggregates of the ␤-amyloid peptide (A␤) is a key pathologic feature during the early stage of Alzheimer's disease. The initial neuronal responses to A␤ in cortical circuits and the regulation of A␤-induced signaling remain unclear. In this study, we found that exposure of cortical slices to A␤ 1-42 or A␤ 25-35 induced a marked increase in the activation of protein kinase C (PKC) and Ca 2؉ /calmodulin-dependent kinase II (CaMKII), two enzymes critically involved in a variety of cellular functions. Activation of M1 muscarinic receptors, but not nicotinic receptors, significantly inhibited the A␤ activation of PKC and CaMKII. Increasing inhibitory transmission mimicked the M1 effect on A␤, whereas blocking GABA A receptors eliminated the M1 action. Moreover, electrophysiological evidence shows that application of A␤ to cortical slices induced action potential firing and enhanced excitatory postsynaptic currents, whereas muscarinic agonists potently increased inhibitory postsynaptic currents. These results suggest that A␤ activates PKC and CaMKII through enhancing excitatory activity in glutamatergic synaptic networks. Activation of M1 receptors inhibits A␤ signaling by enhancing the counteracting GABA ergic inhibitory transmission. Thus the muscarinic reversal of the A␤-induced biochemical and physiological changes provides a potential mechanism for the treatment of Alzheimer's disease with cholinergic enhancers.The 40 -42-amino acid ␤-amyloid peptide (A␤) 1 is a major constituent of senile plaques (1), extracellular protein aggregates that are used as a histopathological hallmark for the diagnosis of Alzheimer's disease (AD). Emerging evidence has suggested that A␤ makes a direct contribution to the pathogenesis of AD (2, 3). A␤ peptides are produced by the cleavage of ␤-amyloid precursor protein (APP) (4). Mutations in the APP gene increases the rate of cleavage, thereby leading to the overproduction of A␤ (5, 6). Transgenic mice overexpressing mutant APP genes exhibit AD-like A␤ deposits and cognition impairments (7-9). In vitro studies in cell lines and cultured neurons show that fibrillar A␤ is neurotoxic at high concentrations (10, 11), and most strikingly, A␤ exposure renders neurons more vulnerable to excitatoxicity (12, 13). Although intensive efforts have been concentrated on factors affecting A␤ production, aggregation, and metabolism (14, 15), little is known about the earliest biochemical and physiological changes in neurons in response to the subtoxic concentrations of A␤, which may be critical for subsequent neurodegenerative changes and the factors that can regulate the A␤-initiated signaling.In addition to A␤ deposits, a prominent feature of AD is the degeneration of basal forebrain cholinergic neurons and ensuing deficient cholinergic functions in their target areas including cortex and hippocampus (16 -18). Despite an improved understanding of the critical role of the cholinergic system in normal cognition and dementia (19,20), it has been largely unclear how cholinergic ...

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Amyloid β peptides act directly on single neurons

Cited by 89 publications

References 7 publications

Acceleration of Amyloid Fibril Formation by Specific Binding of Aβ-(1–40) Peptide to Ganglioside-containing Membrane Vesicles

Acceleration of Amyloid Fibril Formation by Specific Binding of Aβ-(1–40) Peptide to Ganglioside-containing Membrane Vesicles

Oligomeric and fibrillar species of β-amyloid (Aβ42) both impair mitochondrial function in P301L tau transgenic mice

Activation of Muscarinic Receptors Inhibits औ-Amyloid Peptide-induced Signaling in Cortical Slices

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