January 22nd, 2015
Blood-Brain Barrier Damage in Aging
Like all tissues, those of the blood-brain barrier in blood vessel walls deteriorate due to the cellular and molecular damage of aging. Researchers here correlate that deterioration with progressive cognitive impairment, further reinforcing existing data on the contribution of blood vessel functional decline to age-related damage in the brain:
The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD.The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.
>blood vessel walls deteriorate due to the cellular and molecular damage of aging
Yes, but what form of damage? Is it crosslinking of the ECM by AGEs? An inflammatory process? Mechanical fatigue of elastin?
If I may harp on that last item a bit: that's the one acknowledged type of damage that I've never seen SRF put forward a reasonable proposal for correcting.
I think there's a need here for some basic research, enough to at least find out what is the primary type of damage responsible for failure of the BBB.
Hi José,
The breakdown of BBB structure and function with age is a complex process, and will need to be addressed through several rejuvenation biotechnologies.
The first thing to understand is that even talking about BBB "breakdown" is somewhat of a misnomer: much (though by no means all) of it is actually the age-related failure of BBB function (in particular the (dys)regulated loosening of tight junctions, driven by inflammation and oxidative stress), rather than the structural damage implied when one describes the process as a "breakdown." Thus, for instance, Zlokovic has previously shown that inhibition of the inflammatory RAGE pathway blocks the uptake of systemic beta-amyloid at the BBB. The editorial accompanying Zlokovic's new study by Iadecola ("Dangerous Leaks: Blood-Brain Barrier Woes in the Aging Hippocampus") has some suggestions in this direction, and Iadecola himself has already reported some changes in inflammatory function in the choroid plexus (the main player in the blood-spinal cord barrier, which serves a similar function as the BBB and is structurally substantially contiguous with it) that can be reversed by heterochronic parabiosis in mice (although he did not examine barrier function in this study). So it may be that we get a substantial normalization of BBB and BCSB function "for free" when we repair other forms of aging damage (clearance of senescent cells, immunorejuvenation, etc) and thereby abrogate the downstream inflammatory abnormalities.
Also, several studies report that a lot of BBB dysfunction in aging and AD is wrought by hypertension; one of these (yet another report from Zlokovic's group) finds that "Hypertension Induces Brain β-Amyloid Accumulation, Cognitive Impairment, and Memory Deterioration Through Activation of Receptor for Advanced Glycation End Products [RAGE] in Brain Vasculature" in wild-type mice (ie, no Abeta-inducing transgenes). In this model, Zlokovic found that "High Blood Pressure Induces AD by Activating RAGE Through Oxidative Stress and Glycation Product Formation," not via structural damage, and inhibition of RAGE or blockage of oxidative stress protected from hypertension-induced Alzheimer pathology, as showed by rescue from cognitive impairment and parenchymal Aβ deposition," which suggests that in addition to abrogating oxidative and inflammatory stress via repair of other aging damage, prevention or reversal of the age-related rise in systolic BP via damage-repair strategies to reverse arterial stiffening might prevent or even partially reverse the accompanying BBB dysfunction.
Finally (and saving the best for last), in mouse models at least, vaccination against beta-amyloid allows the body to repair the dysfunctional BBB, offering yet another benefit to immunotherapeutic clearance of beta-amyloid.
Hello Michael,
Thank you for the thorough and well-referenced response, as usual demonstrating how SRF stays on top of the latest developments.