The APOE ε4/ε4 Genotype Potentiates Vascular Fibrin(Ogen) Deposition in Amyloid-Laden Vessels in the Brains of Alzheimer's Disease Patients

Abstract

Evidence indicates a critical role for cerebrovascular dysfunction in Alzheimer's disease (AD) pathophysiology. We have shown that fibrin(ogen), the principal blood-clotting protein, is deposited in the AD neurovasculature and interacts with beta-amyloid (Aβ), resulting in increased formation of blood clots. As apolipoprotein E (ApoE), a lipid-transporting protein with three human isoforms (E2, E3, and E4), also binds to Aβ, we hypothesized that ApoE and fibrin(ogen) may have a combined effect on the vascular pathophysiology in AD. We assessed whether APOE genotype differentially influences vascular fibrin(ogen) deposition in postmortem brain tissue using immunohistochemistry. An increased deposition of fibrin(ogen) was observed in AD cases compared with non-demented controls, and there was a strong correlation between cerebral amyloid angiopathy (CAA) severity and fibrin(ogen) deposition. Moreover, brains from AD cases homozygous for APOE ɛ4 showed increased deposition of fibrin(ogen), specifically in CAA- and oligomeric Aβ-positive vessels compared with AD APOE ɛ2 and ɛ3 allele carriers, an effect that was not directly linked to CAA severity and cerebrovascular atherosclerosis. These data further support a role for fibrin(ogen) in AD pathophysiology and link the APOE ɛ4/ɛ4 genotype with increased thrombosis and/or impaired fibrinolysis in the human AD brain.

Pericytes of the neurovascular unit: key functions and signaling pathways

“…Increases in CypA and MMP-9 CSF levels were recently reported to correlate with BBB breakdown in human APOE4 carriers, but not age-matched APOE2 or APOE3 carriers that have an intact BBB 49 . Additionally, post-mortem analysis in APOE4 -positive AD patients compared to non-carriers revealed increased CypA and MMP-9 protein levels in hippocampal and cortical pericytes as well as pericyte degeneration 50,151 .…”

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

“…Several studies of post-mortem brain tissue from patients with AD have found (using various analysis methods: immunohistochemistry, immunoblotting and Prussian blue staining) capillary leakages of blood-derived proteins in the prefrontal and entorhinal cortex and hippocampus, including accumulations of fibrinogen, thrombin, albumin, IgG, and iron-containing proteins such as haemosiderin 146,147,152–157 . These blood-derived proteins are often found co-localized with deposits of AD-associated Aβ 147,153,155 .…”

“…These blood-derived proteins are often found co-localized with deposits of AD-associated Aβ 147,153,155 . Evidence of BBB breakdown is most pronounced in individuals carrying the APOE*ε4 allele, the major genetic risk factor for AD.…”

Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke

“…In fact, multiple studies demonstrated loss of cerebrovascular integrity and BBB damage, for example, on aging and in Alzheimer's disease, 18,20,21 that is accelerated by the apolipoprotein E4 (APOE4) genotype. 18,[21][22][23][24] Mechanistic studies using murine transgenic models showed that APOE4 increases BBB susceptibility to injury 25 and leads to BBB breakdown and microvascular reductions in humanized transgenic APOE4-knock-in mice compared with APOE3-knock-in mice.…”

“…18,[21][22][23][24] Mechanistic studies using murine transgenic models showed that APOE4 increases BBB susceptibility to injury 25 and leads to BBB breakdown and microvascular reductions in humanized transgenic APOE4-knock-in mice compared with APOE3-knock-in mice. 26,27 The present study has been designed to test these hypotheses in patients having acute ischemic stroke in the middle cerebral artery (MCA) territory.…”