Cerebral blood flow (CBF) reductions in Alzheimer’s disease (AD) patients and related mouse models have been recognized for decades, but the underlying mechanisms and resulting consequences on AD pathogenesis remain poorly understood. In APP/PS1 and 5xFAD mice we found that an increased number of cortical capillaries had stalled blood flow as compared to wildtype animals, largely due to neutrophils that adhered in capillary segments and blocked blood flow. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to an immediate increase in CBF and to rapidly improved performance in spatial and working memory tasks. This study identified a novel cellular mechanism that explains the majority of the CBF reduction seen in two mouse models of AD and demonstrated that improving CBF rapidly improved short-term memory function. Restoring cerebral perfusion by preventing neutrophil adhesion may provide a novel strategy for improving cognition in AD patients.

Summary Alzheimer's disease (AD) is a neurodegenerative disorder in which vascular pathology plays an important role. Since the β-amyloid peptide (Aβ) is a critical factor in this disease, we examined its relationship to fibrin clot formation in AD. In vitro and in vivo experiments showed that fibrin clots formed in the presence of Aβ are structurally abnormal and resistant to degradation. Fibrin(ogen) was observed in blood vessels positive for amyloid in mouse and human AD samples, and intravital brain imaging of clot formation and dissolution revealed abnormal thrombosis and fibrinolysis in AD mice. Moreover, depletion of fibrinogen lessened cerebral amyloid angiopathy pathology and reduced cognitive impairment in AD mice. These experiments suggest that one important contribution of Aβ to AD is via its effects on fibrin clots, implicating fibrin(ogen) as a potential critical factor in this disease.

Increasing evidence supports a vascular contribution to Alzheimer's disease (AD), but a direct connection between AD and the circulatory system has not been established. Previous work has shown that blood clots formed in the presence of the β-amyloid peptide (Aβ), which has been implicated in AD, have an abnormal structure and are resistant to degradation in vitro and in vivo. In the present study, we show that Aβ specifically interacts with fibrinogen with a K d of 26.3 ± 6.7 nM, that the binding site is located near the C terminus of the fibrinogen β-chain, and that the binding causes fibrinogen to oligomerize. These results suggest that the interaction between Aβ and fibrinogen modifies fibrinogen's structure, which may then lead to abnormal fibrin clot formation. Overall, our study indicates that the interaction between Aβ and fibrinogen may be an important contributor to the vascular abnormalities found in AD. A lzheimer's disease (AD) is a neurodegenerative disorder that leads to progressive cognitive decline and subsequent death. Effective long-term treatments and preventive measures are not available, and new therapeutic targets are needed. Substantial evidence indicates that the β-amyloid (Aβ) peptide, which is derived from the Aβ precursor protein (APP), is involved in AD (1-3). Aβ is soluble in its monomeric or oligomeric states, but can aggregate into fibrils and deposit as extracellular plaques in the brain parenchyma. However, the severity of dementia does not correlate well with the amount of extracellular amyloid plaques and the mechanism by which Aβ causes neurodegeneration is still unclear (4).Aβ can also accumulate in brain blood vessels, a condition known as cerebral amyloid angiopathy (CAA). CAA is characterized by deposition of Aβ within cerebral vessels, resulting in degenerative vascular changes (5-7). In mouse models of AD, endothelial cells in CAA vessels show early dysfunction, which reduces their response to vasodilators (8) and impairs the regulation of blood flow (9, 10). Many patients with AD present vascular symptoms, including altered cerebral blood flow, damaged cerebral vasculature, and abnormal hemostasis (11). Cerebral blood flow is reduced and many vascular defects are present in patients with AD (12). Vascular diseases such as atherosclerosis correlate in severity with dementia and other symptoms of sporadic AD (13-15). Vascular abnormalities could therefore play an important role in AD, but a direct connection remains unknown.Fibrinogen is the primary protein component of blood clots. It is 45 nm in length with identical globular domains at each end, which are connected by rod-like strands. It is composed of three pairs of polypeptide chains, designated Aα, Bβ, and γ, which are connected by disulfide bonds (16). When fibrinopeptides A and B of fibrinogen are cleaved by the serine protease thrombin, fibrinogen noncovalently polymerizes to form protofibrils, which then branch to form an insoluble fibrin clot. This clot network forms a mesh around platelets to impede blood fl...

Alzheimer’s disease, the leading cause of dementia in the elderly, is a neurodegenerative condition characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, age-related vascular changes accompany or even precede the development of Alzheimer’s pathology, raising the possibility that they may have a pathogenic role. This review provides an appraisal of the alterations in cerebral and systemic vasculature, the heart, and hemostasis that occur in Alzheimer’s disease and their relationships to cognitive impairment. Although the molecular pathogenesis of these alterations remains to be defined, amyloid-β is a likely contributor in the brain as in the heart. Collectively, the evidence suggests that vascular pathology is a likely pathogenic contributor to age-related dementia, including Alzheimer’s disease, inextricably linked to disease onset and progression. Consequently, the contribution of vascular factors should be considered in preventive, diagnostic, and therapeutic approaches to address one of the major health challenges of our time.