Aβ peptides can enter the brain through a defective blood-brain barrier and bind selectively to neurons

New Jersey Institute for Successful Aging, University of Medicine and Dentistry of New Jersey/SOM, 2 Medical Center Drive, Stratford, NJ 08084, USA.
Brain Research (Impact Factor: 2.84). 05/2007; 1142(1):223-36. DOI: 10.1016/j.brainres.2007.01.070
Source: PubMed


We have investigated the possibility that soluble, blood-borne amyloid beta (Abeta) peptides can cross a defective blood-brain barrier (BBB) and interact with neurons in the brain. Immunohistochemical analyses revealed extravasated plasma components, including Abeta42 in 19 of 21 AD brains, but in only 3 of 13 age-matched control brains, suggesting that a defective BBB is common in AD. To more directly test whether blood-borne Abeta peptides can cross a defective BBB, we tracked the fate of fluorescein isothiocyanate (FITC)-labeled Abeta42 and Abeta40 introduced via tail vein injection into mice with a BBB rendered permeable by treatment with pertussis toxin. Both Abeta40 and Abeta42 readily crossed the permeabilized BBB and bound selectively to certain neuronal subtypes, but not glial cells. By 48 h post-injection, Abeta42-positive neurons were widespread in the brain. In the cerebral cortex, small fluorescent, Abeta42-positive granules were found in the perinuclear cytoplasm of pyramidal neurons, suggesting that these cells can internalize exogenous Abeta42. An intact BBB (saline-injected controls) blocked entry of blood-borne Abeta peptides into the brain. The neuronal subtype selectivity of Abeta42 and Abeta40 was most evident in mouse brains subjected to direct intracranial stereotaxic injection into the hippocampal region, thereby bypassing the BBB. Abeta40 was found to preferentially bind to a distinct subset of neurons positioned at the inner face of the dentate gyrus, whereas Abeta42 bound selectively to the population of large neurons in the hilus region of the dentate gyrus. Our results suggest that the blood may serve as a major, chronic source of soluble, exogenous Abeta peptides that can bind selectively to certain subtypes of neurons and accumulate within these cells.

Download full-text


Available from: Michael Robert D'Andrea, Feb 12, 2014
  • Source
    • "The associated pathologic changes in the parenchymal small arteries and arterioles (e.g., arteriolosclerotic changes such as fibrinoid necrosis, lipohylinosis, microatheroma, and microaneurysms) extend to the endothelial barriers of the small vessels and capillaries (i.e., the BBB) resulting in permeability changes and extravasation of plasma components into the vessel walls and brain parenchyma [19]. Postmortem analyses of AD brain tissue have demonstrated changes to the microvasculature through the presence of extravasated serum proteins, such as albumin and immunoglobulin [20] [21] [22] [23], as well as white matter lesions and the widespread deposition of cerebral amyloid angiopathy, with associated microbleeds; all of which may contribute to decline in vascular integrity and function [19]. These observations, together with the findings from the nonclinical models, informed on the choice of AD subjects with neuroimaging evidence of CVD (e.g., white matter lesions and/or lacunes, typical of SVD) in the present study. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The lipoprotein-associated phospholipase A2 inhibitor (Lp-PLA2), rilapladib (SB659032), is being evaluated as a potential treatment to slow the progression of Alzheimer's disease (AD). Methods One hundred twenty-four subjects with possible mild AD and with neuroimaging evidence of cerebrovascular disease were randomized to placebo or 250-mg rilapladib once daily, for 24 weeks, in addition to stable background acetylcholinesterase inhibitor and/or memantine. The study assessed the safety and tolerability of rilapladib and its effects on cognition, mechanistic, and disease-related biomarkers. Although the overall intent behind the study was to take a broad exploratory view of the data, two primary end points of interest (cerebrospinal fluid [CSF] amyloid beta peptide 1-42 [Aβ1-42] and CogState executive function/working memory [EF/WM] composite score at week 24) were prespecified in the analysis plan for inferential statistical analysis. Results Rilapladib was well tolerated with no significant safety concerns. A significant difference from placebo was observed for rilapladib on change from baseline in EF/WM (effect size, 0.45; P =.026). There was no significant difference between groups on the change from baseline in CSF Aβ1-42 (P =.133). Preliminary evidence of effects was detected on other mechanistic (albumin quotient) and disease-related biomarkers (tau/P-tau and neurofilament light chain). Conclusion These data provide initial evidence supporting Lp-PLA2 inhibition as a novel treatment for dementia. Clinical Trial Registration identifier: NCT01428453.
    Preview · Article · Jun 2015
  • Source
    • "Animal studies have shown that CI can stimulate mRNA expression of amyloid precursor protein (APP) and APP proteolytic processing to β-amyloid protein (Aβ), a central neuro-toxic/degenerative factor in AD pathogenesis [17], [18]. Disruption of the blood-brain-barrier (BBB) caused by CI may also increase the extravasation of soluble Aβ peptides, as well as its precursor APP, into the brain parenchyma, resulting in a neuroinflammatory reaction and Aβ plaque formation [19], [20]. In turn, Aβ accumulation can reduce brain capillary density and cause aberration of capillary structures, decreasing local cerebral perfusion [21]–[25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background/Objective Clinical evidence indicates that cerebral ischemia (CI) and a pathological factor of Alzheimer's disease, the β-amyloid (Aβ) protein, can increase the rate of cognitive impairment in the ageing population. Using the CT Perfusion (CTP) functional imaging, we sought to investigate the interaction between CI and the Aβ protein on cerebral hemodynamics. Methods A previously established rat model of CI and Aβ was used for the CTP study. Iodinated contrast was given intravenously, while serial CT images of sixteen axial slices were acquired. Cerebral blood flow (CBF) and blood volume (CBV) parametric maps were co-registered to a rat brain atlas and regions of interest were drawn on the maps. Microvascular alteration was investigated with histopathology. Results CTP results revealed that ipsilateral striatum of Aβ+CI and CI groups showed significantly lower CBF and CBV than control at the acute phase. Striatal CBF and CBV increased significantly at week 1 in the CI and Aβ+CI groups, but not in the Aβ alone or control group. Histopathology showed that average density of dilated microvessels in the ipsilateral striatum in CI and Aβ+CI groups was significantly higher than control at week 1, indicating this could be associated with hyperperfusion and hypervolemia observed from CTP results. Conclusion These results demonstrate that CTP can quantitatively measure the hemodynamic disturbance on CBF and CBV functional maps in a rat model of CI interacting with Aβ.
    Full-text · Article · Jun 2014 · PLoS ONE
  • Source
    • "Intraneuronal Ab has been observed in the brains of AD patients (Gouras et al., 2000) as well as in mouse models of AD (Billings et al., 2005) before the appearance of extracellular plaques. It is possible that at least some of this intraneuronal Ab has been taken up from extracellular Ab pools, especially in light of the observation that fluorescently labeled Ab injected into the tail veins of mice with a compromised blood-brain barrier accumulates in neurons in the cerebral cortex (Clifford et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Insight into how amyloid β (Aβ) aggregation occurs in vivo is vital for understanding the molecular pathways that underlie Alzheimer's disease and requires new techniques that provide detailed kinetic and mechanistic information. Using noninvasive fluorescence lifetime recordings, we imaged the formation of Aβ(1-40) and Aβ(1-42) aggregates in live cells. For both peptides, the cellular uptake via endocytosis is rapid and spontaneous. They are then retained in lysosomes, where their accumulation leads to aggregation. The kinetics of Aβ(1-42) aggregation are considerably faster than those of Aβ(1-40) and, unlike those of the latter peptide, show no detectable lag phase. We used superresolution fluorescence imaging to examine the resulting aggregates and could observe compact amyloid structures, likely because of spatial confinement within cellular compartments. Taken together, these findings provide clues as to how Aβ aggregation may occur within neurons.
    Full-text · Article · May 2014 · Chemistry & Biology
Show more