Laminin blocks the assembly of wild-type Aβ and the Dutch variant peptide into Alzheimer's fibrils

Bronfman, Francisca C.; Álvarez, Alejandra; Morgan, Carlos; Inestrosa, Nibaldo C.

doi:10.3109/13506129809007285

Cited by 35 publications

(20 citation statements)

References 30 publications

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“…Laminin, nidogens, and collagen IV are vascular basement membrane proteins that inhibit aggregation of Ab and destabilize preformed fibrils of Ab (Bronfman et al, 1998). Vessels under 50 lm in diameter from AD patients show a decrease in the amount of collagen IV, compared with aged-matched controls (Christov et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence suggest that biochemical and morphological alterations to basement membranes contribute to the development of CAA. In vitro incubation of Ab with laminin, collagen IV, and nidogen has been shown to prevent Ab fibrillization, whereas agrin and perlecan promote and stabilize Ab fiber formation (Castillo et al, 1997;Bronfman et al, 1998;Cotman et al, 2000;Kiuchi et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

et al. 2013

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SummaryDevelopment of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is associated with failure of elimination of amyloid-b (Ab) from the brain along perivascular basement membranes that form the pathways for drainage of interstitial fluid and solutes from the brain. In transgenic APP mouse models of AD, the severity of cerebral amyloid angiopathy is greater in the cerebral cortex and hippocampus, intermediate in the thalamus, and least in the striatum. In this study we test the hypothesis that age-related regional variation in (1) vascular basement membranes and (2) perivascular drainage of Ab contribute to the different regional patterns of CAA in the mouse brain. Quantitative electron microscopy of the brains of 2-, 7-, and 23-month-old mice revealed significant age-related thickening of capillary basement membranes in cerebral cortex, hippocampus, and thalamus, but not in the striatum. Results from Western blotting and immunocytochemistry experiments showed a significant reduction in collagen IV in the cortex and hippocampus with age and a reduction in laminin and nidogen 2 in the cortex and striatum. Injection of soluble Ab into the hippocampus or thalamus showed an agerelated reduction in perivascular drainage from the hippocampus but not from the thalamus. The results of the study suggest that changes in vascular basement membranes and perivascular drainage with age differ between brain regions, in the mouse, in a manner that may help to explain the differential deposition of Ab in the brain in AD and may facilitate development of improved therapeutic strategies to remove Ab from the brain in AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

et al. 2013

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“…Similarly to AChE, we have also found that the extracellular matrix protein laminin, which is located peripherally to amyloid deposits in experimental rat models, inhibits the process of A fibril formation [31,32] and even may disaggregate amyloid fibrils in vitro [5]. In the Fig.…”

Section: Lamininmentioning

confidence: 92%

Structure-Function Implications in Alzheimers Disease: Effect of Aβ Oligomers at Central Synapses

Cerpa¹,

Dinamarca²,

Inestrosa³

2008

CAR

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Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the growing population of elderly people. A characteristic of AD is the accumulation of plaques in the brain of AD patients, and theses plaques mainly consist of aggregates of amyloid beta-peptide (Abeta). All converging lines of evidence suggest that progressive accumulation of the Abeta plays a central role in the genesis of Alzheimer's disease and it was long understood that Abeta had to be assembled into extracellular amyloid fibrils to exert its cytotoxic effects. This process could be modulated by molecular chaperones which inhibit or accelerate the amyloid formation. The enzyme Acetylcholinesterase (AChE) induces Abeta fibrils formation, forming a stable complex highly neurotoxic. On the other hand, laminin inhibit the Abeta fibrils formation and depolymerizate Abeta fibrils also. Over the past decade, data have emerged from the use of several sources of Abeta (synthetic, cell culture, transgenic mice and human brain) to suggest that intermediate species called Abeta oligomers are also injurious. Accumulating evidence suggests that soluble forms of Abeta are indeed the proximate effectors of synapse loss and neuronal injury. On the other hand, the member of the Wnt signaling pathway, beta-catenin was markedly reduced in AD patients carrying autosomal dominant PS-1. Also, neurons incubated with Abeta revealed a significant dose-dependent decrease in the levels of cytosolic beta-catenin an effect which was reversed in cells co-incubated with increasing concentrations of lithium, an activator of Wnt signaling pathway. Wnt signaling blocks the behavioural impairments induced by hippocampal injection of Abeta, therefore the activation of Wnt signaling protects against the Abeta neurotoxicity. Here we review recent progress about Abeta structure and function, from the formation of amyloid fibrils and some molecular chaperones which modulate the amyloidogenesic process to synaptic damage induce by Abeta oligomers.

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“…Its expression seems to be increased after brain injury (26) and in the brain of AD and Down syndrome patients (27). In order to examine the pathological significance of laminin induction in Alzheimer brains, we studied the effect of laminin on Aß peptide polymerization, and we showed for the first time that laminin was a (28,29). Figure 1A shows a turbidity assay indicating that Aß aggregation in the presence of laminin was clearly decreased, and that the formation of amyloid was also diminished in the presence of laminin, as evidenced by Congo red staining ( Figure 1B).…”

Section: The Anti-amyloidogenic Role Of Lamininmentioning

confidence: 99%

Interactions of laminin with the amyloid ß peptide: Implications for Alzheimer's disease

Morgan

Inestrosa

2001

Braz J Med Biol Res

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Extensive neuronal cell loss is observed in Alzheimers disease. Laminin immunoreactivity colocalizes with senile plaques, the characteristic extracellular histopathological lesions of Alzheimer brain, which consist of the amyloid ß (Aß) peptide polymerized into amyloid fibrils. These lesions have neurotoxic effects and have been proposed to be a main cause of neurodegeneration. In order to understand the pathological significance of the interaction between laminin and amyloid, we investigated the effect of laminin on amyloid structure and toxicity. We found that laminin interacts with the Aß1-40 peptide, blocking fibril formation and even inducing depolymerization of preformed fibrils. Protofilaments known to be intermediate species of Aß fibril formation were also detected as intermediate species of laminin-induced Aß fibril depolymerization. Moreover, laminin-amyloid interactions inhibited the toxic effects on rat primary hippocampal neurons. As a whole, our results indicate a putative anti-amyloidogenic role of laminin which may be of biological and therapeutic interest for controlling amyloidosis, such as those observed in cerebral angiopathy and Alzheimers disease.

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Laminin blocks the assembly of wild-type Aβ and the Dutch variant peptide into Alzheimer's fibrils

Cited by 35 publications

References 30 publications

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

Structure-Function Implications in Alzheimers Disease: Effect of Aβ Oligomers at Central Synapses

Interactions of laminin with the amyloid ß peptide: Implications for Alzheimer's disease

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Laminin blocks the assembly of wild-type Aβ and the Dutch variant peptide into Alzheimer's fibrils

Cited by 35 publications

References 30 publications

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

Structure-Function Implications in Alzheimers Disease: Effect of A&#946; Oligomers at Central Synapses

Interactions of laminin with the amyloid ß peptide: Implications for Alzheimer's disease

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Structure-Function Implications in Alzheimers Disease: Effect of Aβ Oligomers at Central Synapses