10 Sep 2005

After release, some Aβ is degraded locally, a second fraction leaves the brain through interstitial fluid drainage and along brain arterioles, while another fraction is actively transported by proteins, such as LRP and glycoprotein-P, across the blood-brain barrier (BBB) into systemic circulation. Recent studies binding blood Aβ with antibodies have raised the prospect that brain levels of Aβ could possibly be lowered by a therapy that removes the peptide from the periphery, thus creating a peripheral sink.

Cerebral amyloid angiopathy (CAA) commonly accompanies Alzheimer disease and makes blood vessels prone to hemorrhages. Recent studies indicate that both parenchymal and blood vessel amyloid are released from neurons, not smooth muscle or endothelial cells (glia have not been exhaustively tested), and the site of deposition depends on the species of Aβ. Specifically, Aβ40 aggregates more slowly and tends to do so only after it has accumulated near the vessel wall on its way out of the brain, whereas Aβ42 aggregates more readily and tends to do so on the way through the parenchyma to the nearest blood vessel.

The brain vasculature is now amenable to study with new imaging methods, for example, corrosion casting combined with scanning electron microscopy and computer tomography. This method requires perfusing the brain vasculature with a resin that hardens and leaves behind a cast of the "vascular brain" once all organic tissue is removed. Such studies open up new modes of studying the role of cerebrovascular insufficiencies in the pathogenesis of Alzheimer's and related diseases. It can also address whether vascular changes precede parenchymal changes in given mouse models (see Krucker at al., 2004).

The brain's vasculature is sealed off from its neurons and glia by the blood-brain barrier, which keeps the vast majority of proteins and most small molecules out of the brain and controls the active transport of selected molecules. The role of this system in neurodegeneration remains largely unknown. However, the BBB remains a formidable obstacle to drug development efforts and needs to be taken into account by the increasing number of academic drug discovery efforts. Generally speaking, only lipophilic compounds smaller than 400 Daltons cross effectively. The majority of biologically active small molecules, and certainly promising proteins, remain untapped as drugs due to BBB permeability or efflux problems.

The microvasculature is so dense that a nearby capillary feeds each neuron, meaning that overcoming the BBB is not only necessary but also sufficient to reach neurons effectively. In addition to efforts to design small molecule drugs with favorable BBB properties, an alternative approach to overcoming the permeability problem of the BBB involves making chimeric molecules to exploit BBB transporter proteins. Gene therapy approaches using lipid vectors also show promise. A better understanding of the BBB may come from basic genomics and proteomics research. This area is beginning to open up as new proteomic tools are enabling the profiling of purified BBB cells that are isolated via mechanical means or laser capture microdissection (Shusta, 2005). Improved understanding of the molecular basis of the BBB may also improve the ability to design and test drug candidates.

The choroid plexus is a membrane system at the interface between blood and the cerebrospinal fluid, sometimes called the blood-CSF barrier. Made of a capillary bed surrounded by secretary epithelial cells, the choroid plexus is known primarily for producing the CSF. This poorly understood arm of the BBB requires further study in the context of AD because age-related changes in its function may influence transport of Aβ and other CSF components.

BBB/Brain Vasculature: A Report from Bar Harbor

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