In this study, the impact of STAT3 inhibition on cognition, cerebrovascular function, amyloid pathology, oxidative stress, and neuroinflammation was studied using in vitro and in vivo models of Alzheimer’s disease (AD)-related pathology. Our results demonstrated functional improvements associated with a reduction in neuritic plaques, cerebral amyloid angiopathy (CAA), oxidative stress, and neuroinflammation. Reduction in amyloid precursor protein (APP) processing and attenuation of oxidative modification of lipoprotein receptor related protein-1 (LRP-1) were identified as potential underlying mechanisms. These results demonstrate the broad impact of STAT3 on cognitive functions, parenchymal and vascular amyloid pathology and highlight the therapeutic potential of STAT3 specific inhibition for treatment of AD and CAA.

For details, click here.

In this study, we investigated the potential therapeutic effects of the anti-human APOE antibody HAE-4, which selectively recognizes human APOE that is co-deposited with Aβ in cerebral amyloid angiopathy (CAA) and parenchymal amyloid pathology. In chronically treated 5XE4 mice, HAE-4 reduced Aβ deposition including CAA compared to a control antibody, whereas the anti–Aβ antibody had no effect on CAA. Furthermore, the anti–Aβ antibody exacerbated microhemorrhage severity, which highly correlated with reactive astrocytes surrounding CAA. In contrast, HAE-4 did not stimulate microhemorrhages and instead rescued CAA-induced cerebrovascular dysfunction in leptomeningeal arteries in vivo. HAE-4 not only reduced amyloid but also dampened reactive microglial, astrocytic, and proinflammatory-associated genes in the cortex. These results suggest that targeting APOE in the core of both CAA and plaques could ameliorate amyloid pathology while protecting cerebrovascular integrity and function.

For details, click here.

In this study, we showed that hronic administration of the anti-Aβ₄₀ specific antibody, ponezumab, reduced Aβ accumulation both in leptomeningeal and brain vessels in aged Tg2576 mice. Acute administration of ponezumab triggered a significant and transient increase in interstitial fluid Aβ₄₀ levels in aged Tg2576 mice. A beneficial effect on vascular reactivity following acute administration of ponezumab was also noted, even in vessels where there was severe CAA. These data favor a mechanism that involves rapid removal and/or neutralization of Aβ species that may otherwise be detrimental to normal vessel function.

For details, click here.

In this study, we demonstrated that pharmacological depletion of HSPG in cultured VSMC mitigates Aβ₄₀- and Aβ₄₂-induced oxidative stress. We also found that Aβ₄₀ (but not Aβ₄₂) causes a hypercontractile phenotype in cultured VSMC that likely results from a HSPG-mediated augmentation in intracellular Ca(2+) activity. Taken together, our data indicate that HSPG are critical mediators of Aβ-induced oxidative stress and Aβ₄₀-induced VSMC dysfunction, and suggests HSPG may play a critical core in CAA-induced cerebrovascular dysfunction and CAA pathogenesis. 

For details, click here.

In this study, we showed that the NADPH oxidase inhibitor, apocynin (Apo), and the free radical scavenger, tempol, reduce oxidative stress and improve vessel reactivity in aged Tg2576 mice; the improved cerebrovascular function is due to reduction in CAA formation and a decrease in CAA-induced vasomotor impairment; and antioxidant therapies attenuate CAA-related microhemorrhage. These results indicate oxidative stress is a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage, and suggest that NADPH oxidase-derived oxidative stress is a promising therapeutic target for patients with CAA and Alzheimer's disease.

For details, click here.

In this study, we demonstrated that aged Tg2576 mice have more severe cerebrovascular dysfunction that is CAA dependent, have greater cerebral blood flow compromise during and immediately after middle cerebral artery occlusion, and develop larger infarctions after middle cerebral artery occlusion. These data indicate CAA induces a more severe form of cerebrovascular dysfunction than soluble Aβ alone, leading to intra- and postischemic cerebral blood flow deficits that ultimately exacerbate cerebral infarction.

For details, click here.

In this study, we demonstrated that the phenoxazine derivative, resorufin, preferentially binds CAA (arrowheads) over neuritic plaques (arrows) in aged Tg2576 mice. We also found that resorufin staining was predominantly noted in amyloid-laden vessels in postmortem Alzheimer's brain tissues, and that resorufin selectively visualizes CAA in live Tg2576 mice when topically administered. Resorufin analogs are the fist class of amyloid dye that discriminate between cerebrovascular and neuritic forms of amyloid. This binding selectivity suggests resorufin analogs have great potential as a CAA-specific amyloid tracer that could permit non-invasive detection and quantification of CAA in live patients.

For details, click here.

In this study, we showed that a strong correlation between CAA severity and vessel reactivity exists in Tg2576 mice; a surprisingly small amount of CAA produces marked reduction or complete loss of vessel function; CAA-induced vasomotor impairment results from dysfunction rather than loss or disruption of vascular smooth muscle cells; and acute depletion of Aβ improves vessel function in young and to a lesser degree aged Tg2576 mice. These results suggest soluble and insoluble Aβ causes vasomotor impairment, that mechanisms other than Aβ-induced alteration in vessel integrity are responsible, and that anti-Aβ therapy may have beneficial effects on vascular as well as parenchymal amyloid.

For details, click here.