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
    • "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.
    PLoS ONE 06/2014; 9(6):e100575. DOI:10.1371/journal.pone.0100575 · 3.23 Impact Factor
  • 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.
    Chemistry & Biology 05/2014; 21(6). DOI:10.1016/j.chembiol.2014.03.014 · 6.65 Impact Factor
  • Source
    • "Given the evidence showing increased levels of circulating Aβ within the periphery during AD development, damage to the brain (particularly the hippocampus) might be caused by excessive blood to brain uptake of Aβ through a compromised BBB, again potentially caused, in part, by peripheral elevations of circulating Aβ. The finding that Aβ peptides can enter the brain of rodents from the periphery following pharmacological BBB impairment (Clifford et al., 2007) is also consistent with this possible mechanism. The direct relevance of this model to Alzheimer’s disease onset is further supported by a recent study showing that high fat diet consumption in 3xTg-AD mice increased Aβ accumulation in the hippocampus (Barron et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Both obesity and Alzheimer's disease (AD) are major health burdens in Western societies. While commonly viewed as having separate etiologies, this review highlights data suggesting that intake of "Western diets", diets high in saturated fatty acids (SFA) and simple carbohydrates, may pose a common environmental risk factor contributing to the development of both of these adverse pathologies. We discuss the effects of Western Diet intake on learning and memory processes that are dependent on the hippocampus, as well as the importance of this brain region in both obesity development and the onset of Alzheimer's and other dementias. A putative mechanism is discussed that mechanistically links Western diet consumption, blood brain barrier (BBB) degradation, and subsequent hippocampal damage and dementia pathology.
    Frontiers in Aging Neuroscience 05/2014; 6:88. DOI:10.3389/fnagi.2014.00088 · 4.00 Impact Factor
Show more