Production and increased detection of amyloid beta protein and amyloidogenic fragments in brain microvessels, meningeal vessels and choroid plexus in Alzheimer's disease.
Recent advances indicate soluble amyloid beta (A beta) protein is produced constitutively during normal metabolism of the amyloid precursor protein (APP). This has not been directly examined in human brain vascular tissues. Using a panel of well-characterized antibodies, here we show that increased amounts of soluble A beta were found in isolated vascular tissues from AD subjects compared to age-matched controls without significant Alzheimer pathology. Immunocytochemical analyses of isolated vessel preparations showed characteristic transverse patterns of A beta deposits in large vessels with smooth muscle, however, fine A beta deposits were apparent even in capillaries. A proportion of such A beta protein and potentially amyloidogenic carboxyl terminal fragments were released by solubilization and disruption of the vascular basement membrane by collagenase treatments. We further demonstrated by in vitro metabolic labelling that soluble A beta or an A beta-like peptide is associated and produced by cerebral microvessels, meningeal vessels and the choroid plexus isolated postmortem from human as well as rat brain. Compared to those from young rats, cerebral microvessels from aging rats showed increased release of carboxyl terminal fragments of APP and A beta-like peptide. Our observations provide the first direct demonstration that human vascular tissues produce soluble A beta, a product of the secretory pathway in APP processing. Our findings also suggest that aging associated alterations in the basement membranes are a factor in A beta accumulation that results in vascular amyloid deposition, the principal feature of cerebral amyloid angiopathy.
Kalaria
R N
RN
Department of Neurology, Case Western Reserve University, Cleveland, OH 44106, USA.
Premkumar
D R
DR
Pax
A B
AB
Cohen
D L
DL
Lieberburg
I
I
D000368:Aged; D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000254:growth & development / Q000378:metabolism; D002560:Cerebrovascular Circulation; D002831:Choroid Plexus / Q000098:blood supply*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008578:Meninges / Q000098:blood supply*; D008833:Microcirculation / Q000378:metabolism*; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments