Alzheimer’s Disease—is it Caused by Cerebrovascular Dysfunction?

2009 ◽  
pp. 369-384
Author(s):  
Christian Humpel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrovascular Dysfunction

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

2013 ◽  
Vol 33 (8) ◽  
pp. 1251-1258 ◽  
Author(s):  
Karin Hultman ◽  
Sidney Strickland ◽  
Erin H Norris
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Critical Role ◽  
Apoe Genotype ◽  
Postmortem Brain ◽  
Amyloid Angiopathy ◽  
Apoe Ε4 ◽  
Cerebrovascular Dysfunction ◽  
Postmortem Brain Tissue ◽  
Clotting Protein

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 (Ab), 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 ε4 showed increased deposition of fibrin(ogen), specifically in CAA- and oligomeric Aβ-positive vessels compared with AD APOE ε2 and ε3 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 ε4/ε4 genotype with increased thrombosis and/or impaired fibrinolysis in the human AD brain.

scholarly journals NITRIC OXIDE SYNTHASE DYSFUNCTION UNDERLIES CEREBROVASCULAR DEFICITS IN A MOUSE MODEL OF TAUOPATHY

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S91-S91
Author(s):  
Candice E Van Skike ◽  
Stacy A Hussong ◽  
Andy Banh ◽  
Veronica Galvan
Keyword(s):  
Nitric Oxide ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Nitric Oxide Synthase ◽  
Mouse Model ◽  
Doppler Flowmetry ◽  
Cerebrovascular Dysfunction ◽  
Oxide Synthase

Abstract We recently identified pathogenic soluble aggregated tau (tau oligomers) in the cerebral microvasculature of human patients with tauopathies, including Alzheimer’s disease (AD). The functional consequences of cerebrovascular tau accumulation are not yet understood. The aim of the present study was to determine whether pathogenic tau accumulation leads to cerebrovascular dysfunction. To this end, we measured neurovascular coupling (NVC), a highly regulated process that synchronizes cerebral blood flow to neuronal activation, using the PS19(P301S) mouse model of tauopathy. The change in cerebral blood flow evoked by whisker stimulation was measured using Laser Doppler flowmetry in PS19 and wildtype control mice and the functional contribution of neuronal and endothelial nitric oxide synthase (nNOS and eNOS, respectively) was calculated. Vascular reactivity was assessed using topical acetylcholine to evoke endothelium-dependent vasodilation. To assess the direct impact of pathogenic tau on cell-specific NOS function, we treated N2a neuroblastoma cells or mouse brain vascular endothelial cells with soluble tau aggregates and measured activity of nNOS and eNOS. Our data indicate isolated overexpression of mutant tau impairs NVC responses, and this deficit is mediated by a reduction in nNOS activity in vivo. Further, our studies suggest tauopathy also impairs endothelium-dependent vasoreactivity in the cortex. Additionally, soluble tau aggregates inhibit the phosphorylation of NOS in primary cultured cells. Therefore, inhibition of NOS phosphorylation by pathogenic soluble tau aggregates may underlie cerebrovascular dysfunction in tauopathies. Thus, therapeutic modulation of pathogenic tau may mitigate brain microvascular deficits, which occur prior to clinical onset in Alzheimer’s disease and potentially other tauopathies.

O3-14-05: ASSOCIATIONS OF CSF BIOMARKERS OF NEUROINFLAMMATION AND CEREBROVASCULAR DYSFUNCTION WITH ALZHEIMER'S DISEASE PATHOLOGY AND CLINICAL PROGRESSION

2006 ◽  
Vol 14 (7S_Part_19) ◽  
pp. P1061-P1061
Author(s):  
Shorena Janelidze ◽  
Niklas Mattsson ◽  
Erik Stomrud ◽  
Olof Lindberg ◽  
Sebastian Palmqvist ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Csf Biomarkers ◽  
Clinical Progression ◽  
Cerebrovascular Dysfunction

scholarly journals Impact of the Coagulation System on the Pathogenesis of Alzheimer's Disease

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-3-SCI-3
Author(s):  
Sidney Strickland
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Conflicts Of Interest ◽  
Neuronal Degeneration ◽  
Neuronal Loss ◽  
Vascular Pathology ◽  
Coagulation System ◽  
Cerebrovascular Dysfunction ◽  
Aging Populations ◽  
Coagulation Pathway

Abstract Alzheimer's disease (AD) leads to cognitive impairment and is eventually fatal. The cognitive decline is associated with extensive neuronal degeneration. The most well-known pathological features of AD are extracellular Aβ plaques, intracellular tau tangles, neuroinflammation, and neuronal loss. Less discussed is that AD is often associated with cerebrovascular abnormalities. The symptoms of AD and cerebrovascular pathology could be independent co-morbidities, with both being increased in aging populations. However, it is also possible that there is a mechanistic link between AD and vascular pathology. The interaction of Aβ with fibrin(ogen) can lead to increased fibrin deposition in cerebral blood vessels, and these accumulated fibrin deposits may disrupt cerebral blood flow and induce microinfarcts, inflammation, and BBB damage, all of which are aspects of cerebrovascular dysfunction observed in AD. At the same time, Ab's ability to activate FXII may contribute to increased fibrin generation through the intrinsic coagulation pathway as well as to increased inflammation and vascular permeability through bradykinin release from HK. These possible roles of Aβ in thrombosis, fibrinolysis, and inflammation via its interaction with fibrinogen and FXII, summarized in Figure 1, will be discussed. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impaired Hippocampal Neurovascular Coupling in a Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Lin Li ◽  
Xin-Kang Tong ◽  
Mohammadamin Hosseini Kahnouei ◽  
Diane Vallerand ◽  
Edith Hamel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Synaptic Transmission ◽  
Ex Vivo ◽  
Neurovascular Unit ◽  
Neurovascular Coupling ◽  
Vascular Response ◽  
Vascular Responses ◽  
Cerebrovascular Dysfunction

Alzheimer’s disease (AD), the most common form of dementia, is characterized by neuronal degeneration and cerebrovascular dysfunction. Increasing evidence indicates that cerebrovascular dysfunction may be a key or an aggravating pathogenic factor in AD. This emphasizes the importance to investigate the tight coupling between neuronal activity and cerebral blood flow (CBF) termed neurovascular coupling (NVC). NVC depends on all cell types of the neurovascular unit within which astrocytes are important players in the progression of AD. Hence, the objective of this study was to characterize the hippocampal NVC in a mouse model of AD. Hippocampal NVC was studied in 6-month-old amyloid-beta precursor protein (APP) transgenic mice and their corresponding wild-type littermates using in vivo laser Doppler flowmetry to measure CBF in area CA1 of the hippocampus in response to Schaffer collaterals stimulation. Ex vivo two-photon microscopy experiments were performed to determine astrocytic Ca2+ and vascular responses to electrical field stimulation (EFS) or caged Ca2+ photolysis in hippocampal slices. Neuronal synaptic transmission, astrocytic endfeet Ca2+ in correlation with reactive oxygen species (ROS), and vascular reactivity in the presence or absence of Tempol, a mimetic of superoxide dismutase, were further investigated using electrophysiological, caged Ca2+ photolysis or pharmacological approaches. Whisker stimulation evoked-CBF increases and ex vivo vascular responses to EFS were impaired in APP mice compared with their age-matched controls. APP mice were also characterized by decreased basal synaptic transmission, a shorter astrocytic Ca2+ increase, and altered vascular response to elevated perivascular K+. However, long-term potentiation, astrocytic Ca2+ amplitude in response to EFS, together with vascular responses to nitric oxide remained unchanged. Importantly, we found a significantly increased Ca2+ uncaging-induced ROS production in APP mice. Tempol prevented the vascular response impairment while normalizing astrocytic Ca2+ in APP mice. These findings suggest that NVC is altered at many levels in APP mice, at least in part through oxidative stress. This points out that therapies against AD should include an antioxidative component to protect the neurovascular unit.

scholarly journals Alzheimer's Disease: Cerebrovascular Dysfunction, Oxidative stress, and Advanced Clinical Therapies

2008 ◽  
Vol 15 (2) ◽  
pp. 199-210 ◽  
Author(s):  
Michael W. Marlatt ◽  
Paul J. Lucassen ◽  
George Perry ◽  
Mark A. Smith ◽  
Xiongwei Zhu
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrovascular Dysfunction

scholarly journals Potential Role of Venular Amyloid in Alzheimer’s Disease Pathogenesis

2020 ◽  
Vol 21 (6) ◽  
pp. 1985 ◽  
Author(s):  
Christopher D. Morrone ◽  
Jossana Bishay ◽  
JoAnne McLaurin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Strong Association ◽  
Cerebrovascular Diseases ◽  
Amyloid Angiopathy ◽  
Perivascular Spaces ◽  
Amyloid Beta Peptides ◽  
Cerebral Vessel ◽  
Beta Peptides ◽  
Cerebrovascular Dysfunction

Insurmountable evidence has demonstrated a strong association between Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), along with various other cerebrovascular diseases. One form of CAA, which is the accumulation of amyloid-beta peptides (Aβ) along cerebral vessel walls, impairs perivascular drainage pathways and contributes to cerebrovascular dysfunction in AD. To date, CAA research has been primarily focused on arterial Aβ, while the accumulation of Aβ in veins and venules were to a lesser extent. In this review, we describe preclinical models and clinical studies supporting the presence of venular amyloid and potential downstream pathological mechanisms that affect the cerebrovasculature in AD. Venous collagenosis, impaired cerebrovascular pulsatility, and enlarged perivascular spaces are exacerbated by venular amyloid and increase Aβ deposition, potentially through impaired perivascular clearance. Gaining a comprehensive understanding of the mechanisms involved in venular Aβ deposition and associated pathologies will give insight to how CAA contributes to AD and its association with AD-related cerebrovascular disease. Lastly, we suggest that special consideration should be made to develop Aβ-targeted therapeutics that remove vascular amyloid and address cerebrovascular dysfunction in AD.

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