1. Amyloid Beta 25-35 induces blood-brain barrier disruption in vitro
Sumit Sarkar,Manuel A Ramirez-Lee,Susan M Burks,Syed F Ali,Hector Rosas-Hernandez,Elvis Cuevas,Aida Guzman,Syed Z Imam Metab Brain Dis . 2019 Oct;34(5):1365-1374. doi: 10.1007/s11011-019-00447-8.
The amyloid β-peptide (Aβ) is transported across the blood-brain barrier (BBB) by binding with the receptor for advanced glycation end products (RAGE). Previously, we demonstrated that the Aβ fraction 25-35 (Aβ25-35) increases RAGE expression in the rat hippocampus, likely contributing to its neurotoxic effects. However, it is still debated if the interaction of Aβ with RAGE compromises the BBB function in Alzheimer' disease (AD). Here, we evaluated the effects of Aβ25-35in an established in vitro model of the BBB. Rat brain microvascular endothelial cells (rBMVECs) were treated with 20 μM active Aβ25-35or the inactive Aβ35-25(control), for 24 h. Exposure to Aβ25-35significantly decreased cell viability, increased cellular necrosis, and increased the production of reactive oxygen species (ROS), which triggered a decrease in the enzyme glutathione peroxidase when compared to the control condition. Aβ25-35also increased BBB permeability by altering the expression of tight junction proteins (decreasing zonula occludens-1 and increasing occludin). Aβ25-35induced monolayer disruption and cellular disarrangement of the BBB, with RAGE being highly expressed in the zones of disarrangement. Together, these data suggest that Aβ25-35-induces toxicity by compromising the functionality and integrity of the BBB in vitro. Graphical abstract Aβ25-35induces BBB dysfunction in vitro, wich is likely mediated by OS and ultimately leads to disruption of BBB integrity and cell death.
2. beta-Amyloid fragment 25-35 selectively decreases complex IV activity in isolated mitochondria
J B Clark,T E Bates,L Canevari FEBS Lett . 1999 Aug 20;457(1):131-4. doi: 10.1016/s0014-5793(99)01028-5.
Defects in mitochondrial oxidative metabolism, in particular decreased activity of cytochrome c oxidase, have been demonstrated in Alzheimer's disease, and after the expression of the amyloid precursor protein (APP) in cultured cells, suggesting that mitochondria might be involved in beta-amyloid toxicity. Recent evidence suggests that the proteolysis of APP to generate beta-amyloid is at least in part intracellular, preceding the deposition of extracellular fibrils. We have therefore investigated the effect of incubation of isolated rat brain mitochondria with the beta-amyloid fragment 25-35 (100 microM) on the activities of the mitochondrial respiratory chain complexes I, II-III, IV (cytochrome c oxidase) and citrate synthase. The peptide caused a rapid, dose-dependent decrease in the activity of complex IV, white it had no effect on the activities on any of the other enzymes tested. The reverse sequence peptide (35-25) had no effect on any of the activities measured. We conclude that inhibition of mitochondrial complex IV might be a contributing factor to the pathogenesis of Alzheimer's disease.
3. Amyloid beta(1-42) and its beta(25-35) fragment induce in vitro phosphatidylcholine hydrolysis in bovine retina capillary pericytes
M Alberghina,C D Anfuso,G Lupo,R P Strosznajder,G Assero,M Walski,R Pluta Neurosci Lett . 2001 May 11;303(3):185-8. doi: 10.1016/s0304-3940(01)01749-9.
We describe the inhibitory effect of full-length Abeta(1-42) and Abeta(25-35) fragment of amyloid-beta peptide on phosphatidylcholine (PtdCho) metabolism in bovine retina capillary pericytes. Cell cultures were incubated with Abetas for 24 h. Peroxidation indices (malondialdehyde and lactate dehydrogenase release) significantly increased after 20-50 microM Abeta(1-42) or Abeta(25-35) treatment. In addition, [Me-3H]choline incorporation into PtdCho strongly decreased while either 3H-choline or 14C-arachidonic acid release from prelabeled cells increased, indicating PtdCho hydrolysis. The effect was very likely due to prooxidant action of both Abeta peptides. Reversed-sequence Abeta(35-25) peptide did not depress 3H-choline incorporation nor stimulate PtdCho breakdown. With addition of Abetas at low concentrations (2-20 microM) to pericytes, marked ultrastructural changes, well connected to metabolic alterations, emerged including shrinkage of cell bodies, retraction of processes, disruption of the intracellular actin network. Cells treated with higher concentrations (50-200 microM) displayed characteristics of necrotic cell death. The data suggest that: (a) Abeta(1-42) and Abeta(25-35) peptides may modulate phospholipid turnover in microvessel pericytes; (b) together with endothelial cells, pericytes could be the target of vascular damage during processes involving amyloid accumulation.
4. beta-Amyloid(25-35) inhibits the activity of inositol(1,4,5)-trisphosphate-5-phosphatase
C J Fowler,A Rönnbäck Amyloid . 2000 Jun;7(2):90-4. doi: 10.3109/13506120009146244.
beta-amyloid (A beta) peptides are known to disrupt calcium homeostasis in cells. In the present study, the effects of A beta(25-35) upon the activity of soluble Ins(1,4,5)P3-5-phosphatase have been investigated. A beta(25-35) inhibited, and dithiothreitol (DTT) increased the activity of soluble rat cerebellar Ins(1,4,5)P3-5-phosphatase. The change in activity was not accompanied by an obvious change in the sensitivity of the Ins(1,4,5)P3-5-phosphatase to inhibition by glucose-6-phosphate or phytic acid. A beta(35-25) also inhibited soluble Ins(1,4,5)P3-5-phosphatase activity, but at a lower potency than A beta(25-35). It is concluded that A beta(25-35) affects the metabolism of Ins(1,4,5)P3 although the potency is not sufficiently high to contribute to any significant extent to the effects of this peptide upon calcium homeostasis.
