Microvasculature in Brain Biopsy Specimens from Patients with Alzheimer's Disease: An Immunohistochemical and Ultrastructural Study

Abstract

Brain biopsy specimens from five patients with Alzheimer's disease obtained in the course of a trial of intracerebroventricular bethanechol were studied by immunohistochemical (antibody to A4 peptide) and ultrastructural techniques, with particular emphasis on the microvessels. In some cases, numbers of A4-immunoreactive lesions (senile plaques) correlated well with numbers of plaques demonstrable by silver stains. Prominent A4-immunoreactive amyloid angiopathy was seen in one patient. The patient with severe cerebral amyloid angiopathy (CAA) showed extensive arteriolar deposition of amyloid filaments with apparent destruction of the media but remarkably intact endothelium. A cell of origin for amyloid filaments was not apparent, although close proximity to smooth muscle cell remnants in the arteriolar media suggested this as one possible cell of origin. Frequent vessels showed medial or adventitial collagen deposition, even when the amount of amyloid was minimal or negligible. Thus relatively severe CAA can exist in the absence of overt endothelial injury, although related studies on this tissue indicate definite abnormalities of the blood-brain barrier. Conversely, destruction of smooth muscle cells and collagen deposition in vessel walls may be the cellular correlates of arteriolar weakening that can lead to CAA-related brain hemorrhage.

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

“…Arteries become rigid, elongated, and tortuous, while vascular basement membranes show abnormal inclusions, splitting, duplication, and thickening (Wisniewski et al, 1992;Vinters et al, 1994;Kalaria, 2002;Hunter et al, 2012). Increased basement membrane thickness has been observed in brain capillaries of transgenic mice that overexpress TGF-b as early as 4 months of age, approximately 5 months before CAA is detected, suggesting that basement membrane thickening may contribute to Ab deposition (Wyss-Coray et al, 2000).…”

Structural and Functional Disruption of Vascular Smooth Muscle Cells in a Transgenic Mouse Model of Amyloid Angiopathy

“…The SMC loss seen in the Tg2576 mouse model of amyloid deposition parallels that previously described at the ultrastructural level in postmortem human AD cases. 16 Intriguingly, such a model of amyloid-induced SMC dysfunction presents the possibility of restoring vessel function, if the amyloid can be cleared before SMC loss in affected vessels. The development of therapeutic approaches for amyloid clearance 17 should enable the testing of this hypothesis in these animals.…”

Neurovascular function in Alzheimer's disease patients and experimental models

“…Transgenic mice overexpressing constitutively active TGF-b1 in astrocytes (TGF mice) were generated to clarify the role of TGF-b1 increase in AD, and more importantly, to address the cerebrovascular pathology related to the basement membrane (Wyss-Coray et al, 1995). The latter is thickened (Mancardi et al, 1980;Vinters et al, 1994) as a result of accumulation of collagen IV (Kalaria and Pax, 1995) and that of other matrix proteins, a phenomenon associated with high levels of TGF-b1 in AD vessels (Grammas and Ovase, 2002). Transforming growth factor mice feature increased expression of vascular growth factors (vascular endothelial growth factor; connective tissue growth factor), and accumulation of perlecan, fibronectin, laminin, and collagen in the vascular basement membrane that contribute to its thickening (WyssCoray et al, 1995(WyssCoray et al, , 2000Tong et al, 2005;Nicolakakis et al, 2011).…”