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A mechanistic understanding of the pathology of psychiatric disorders has been hampered by extensive heterogeneity in biology, symptoms, and behavior within diagnostic categories that are defined subjectively. We investigated whether leveraging individual differences in information-processing impairments in patients with post-traumatic stress disorder (PTSD) could reveal phenotypes within the disorder. We found that a subgroup of patients with PTSD from two independent cohorts displayed both aberrant functional connectivity within the ventral attention network (VAN) as revealed by functional magnetic resonance imaging (fMRI) neuroimaging and impaired verbal memory on a word list learning task. This combined phenotype was not associated with differences in symptoms or comorbidities, but nonetheless could be used to predict a poor response to psychotherapy, the best-validated treatment for PTSD. Using concurrent focal noninvasive transcranial magnetic stimulation and electroencephalography, we then identified alterations in neural signal flow in the VAN that were evoked by direct stimulation of that network. These alterations were associated with individual differences in functional fMRI connectivity within the VAN. Our findings define specific neurobiological mechanisms in a subgroup of patients with PTSD that could contribute to the poor response to psychotherapy.

Cerebrovascular dysfunction has been implicated as a major contributor to Alzheimer's Disease (AD) pathology, with cerebral endothelial cell (cEC) stress promoting ischemia, cerebral‐blood flow impairments and blood–brain barrier (BBB) permeability. Recent evidence suggests that cardiovascular (CV)/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy), exacerbate AD pathology and risk. Yet, the underlying molecular mechanisms for this interaction remain unclear. Our lab has demonstrated that amyloid beta 40 (Aβ40) species, and particularly Aβ40‐E22Q (AβQ22; vasculotropic Dutch mutant), promote death receptor 4 and 5 (DR4/DR5)‐mediated apoptosis in human cECs, barrier permeability, and angiogenic impairment. Previous studies show that Hhcy also induces EC dysfunction, but it remains unknown whether Aβ and homocysteine function through common molecular mechanisms. We tested the hypotheses that Hhcy exacerbates Aβ‐induced cEC DR4/5‐mediated apoptosis, barrier dysfunction, and angiogenesis defects. This study was the first to demonstrate that Hhcy specifically potentiates AβQ22‐mediated activation of the DR4/5‐mediated extrinsic apoptotic pathway in cECs, including DR4/5 expression, caspase 8/9/3 activation, cytochrome‐c release and DNA fragmentation. Additionally, we revealed that Hhcy intensifies the deregulation of the same cEC junction proteins mediated by Aβ, precipitating BBB permeability. Furthermore, Hhcy and AβQ22, impairing VEGF‐A/VEGFR2 signaling and VEGFR2 endosomal trafficking, additively decrease cEC angiogenic capabilities. Overall, these results show that the presence of the CV risk factor Hhcy exacerbates Aβ‐induced cEC apoptosis, barrier dysfunction, and angiogenic impairment. This study reveals specific mechanisms through which amyloidosis and Hhcy jointly operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in comorbid AD/CAA and Hhcy conditions. [ABSTRACT FROM AUTHOR]

This editorial summarizes advances from the Clearance of Interstitial Fluid and Cerebrospinal Fluid (CLIC) group, within the Vascular Professional Interest Area (PIA) of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART). The overarching objectives of the CLIC group are to: (1) understand the age‐related physiology changes that underlie impaired clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) (CLIC); (2) understand the cellular and molecular mechanisms underlying intramural periarterial drainage (IPAD) in the brain; (3) establish novel diagnostic tests for Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), retinal amyloid vasculopathy, amyloid‐related imaging abnormalities (ARIA) of spontaneous and iatrogenic CAA‐related inflammation (CAA‐ri), and vasomotion; and (4) establish novel therapies that facilitate IPAD to eliminate amyloid β (Aβ) from the aging brain and retina, to prevent or reduce AD and CAA pathology and ARIA side events associated with AD immunotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Cerebrovascular pathology is an early and causal hallmark of Alzheimer's disease (AD), in need of effective therapies. Methods: Based on the success of our previous in vitro studies, we tested for the first time in a model of AD and cerebral amyloid angiopathy (CAA), the carbonic anhydrase inhibitors (CAIs) methazolamide and acetazolamide, Food and Drug Administration–approved against glaucoma and high‐altitude sickness. Results: Both CAIs reduced cerebral, vascular, and glial amyloid beta (Aβ) accumulation and caspase activation, diminished gliosis, and ameliorated cognition in TgSwDI mice. The CAIs also improved microvascular fitness and induced protective glial pro‐clearance pathways, resulting in the reduction of Aβ deposition. Notably, we unveiled that the mitochondrial carbonic anhydrase‐VB (CA‐VB) is upregulated in TgSwDI brains, CAA and AD+CAA human subjects, and in endothelial cells upon Aβ treatment. Strikingly, CA‐VB silencing specifically reduces Aβ‐mediated endothelial apoptosis. Discussion: This work substantiates the potential application of CAIs in clinical trials for AD and CAA. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is characterized‐ at both early and late stages‐ by neurovascular impairment. In AD, dysfunctional cerebral microvasculature is accompanied by an inflammatory response, contributing to Aβ and tau accumulation, brain cell stress and death, impaired clearance of metabolic waste, BBB permeability, and ultimately leading to neuronal demise and cognitive impairment. We previously showed that Aβ peptides induce mitochondrial dysregulation and caspase‐mediated apoptosis in brain cells, including endothelial, glial, and smooth muscle cells. Moreover, we found FDA‐approved carbonic anhydrase inhibitors (CAIs), acetazolamide (ATZ) and methazolamide (MTZ), clinically used for non‐AD related conditions, effectively rescue these pathological events, and ameliorate cognitive impairment, brain amyloidosis, and vascular and glial fitness, in an AD/CAA (Cerebral Amyloid Angiopathy) in vivo model. We unveiled a mitochondrial isoform, Carbonic Anhydrase (CA‐VB), as a major player in Aβ‐mediated toxicity, with increased CA‐VB levels in AD/CAA mouse and human brains. Method: 3xTg mice express three familial AD mutations: Swedish APP mutation (KM670/671NL), PSEN1 M146V mutation, and MAPT P301L mutation. Following 10 month‐CAI‐diet, mice were sacrificed at 16 months of age,. Brains were harvested and processed for biochemical and immunohistochemistry analysis. Result: CAIs ameliorate cognitive dysfunction, and significantly reduce hippocampal and cortical Aβ deposition and Thioflavin S positive deposits in 3xTg mice. Specifically in the hippocampus, CAIs rescue OXPHOS complexes dysregulated expression, reduce mitochondrial CA‐VB expression, and prevent caspase‐3 activation. In hippocampus and cortex, 3xTg present loss of PDGFRβ (microvascular marker) and increased gliosis (GFAP and IBA1), which are rescued by CAIs. Conclusion: CAIs show positive behavioral outcomes in 16‐month‐old 3xTg mice, and reduce brain amyloidosis, compared to untreated animals. In the hippocampus, CAIs foster microvascular health and reduce inflammatory state, and in the cortex, MTZ decreases microgliosis, unveiling cell specific CAI effects underlying Aβ deposition reduction observed in both areas. This work points to CAIs as a potential therapeutic strategy to treat brain microvascular impairment and neuroinflammation, preventing mitochondria‐mediated cell stress and death. [ABSTRACT FROM AUTHOR]

Background: The blood‐brain barrier (BBB) is a crucial regulator of cerebral homeostasis and function. Cerebrovascular endothelial cells (EC) are important components of the BBB, and EC damage and/or dysfunction may result in defects in brain clearance and perfusion, microhemorrhages, inflammation, and neurodegeneration. In addition to EC damage resulting from the presence of amyloid‐beta (Aβ) in Alzheimer's Disease (AD) and Cerebral Amyloid Angiopathy (CAA), the presence of cardiovascular risk factors (CVRF) may further exacerbate cerebrovascular function and neurodegeneration. Particularly, ECs may be the most susceptible to Aβ and CVRF damage leading to the initiation and/or perpetuation of an inflammatory cascade in neurodegenerative diseases. Brain ECs are highly dependent on glycolysis and their mitochondria have important roles as signaling organelles, sensing cellular damage and mediating downstream pathways such as inflammation. Here, we aim to understand the mechanistic nature of endothelial mitochondrial dysfunction and its elicited pathways in Aβ and mixed (Aβ+CVRF) vascular pathologies. Understanding the mechanisms by which the mitochondria may mediate EC inflammation could pave the way to new roads for therapeutic advancements in the field. Method: Human brain microvascular ECs were challenged with Aβ, Homocysteine (Hcy, a CVRF), or the combination. Mitochondrial ultrastructure, metabolic function, and inflammatory cascades were assessed. Result: The presence of Aβ, but not Hcy, increased mitochondrial ROS production (mtROS) and induced deficits in mitochondrial respiration concomitant with a decrease in mitochondrial ATP production. Deficits in mitochondrial respiration were accompanied by an increase in glycolytic ATP production and, to some extent, the expression of proteins involved in glycolytic regulation. Mitochondrial fragmentation, as an indicator of mitochondrial damage, was assessed ultrastructually and by the analysis of the expression of fission proteins. Markers of EC activation were assessed to link mitochondrial dysfunction to EC inflammation. Conclusion: Deficits in mitochondrial function and metabolism were associated with Aβ but not Hcy, and accompanied by the release of mtROS, a mitochondria damage associated molecular patterns (mtDAMP). This, in turn, was associated to an increase in EC inflammatory markers and barrier permeability. Overall, our results reveal a novel role for mtDAMPs in vascular dysfunction in the presence of Aβ and/or Hcy. [ABSTRACT FROM AUTHOR]

Background: Neurofibrillary tangles formed by hyperphosphorylated tau aggregates in the brain are one of the classical hallmarks of Alzheimer's Disease (AD). Tau aggregates have been shown to elicit cytotoxicity, leading to overall neuronal loss and cognitive decline in AD. These aggregates can be transmitted from neurons and glial cells to other brain cells through a process known as tau spreading, and ultimately reach the endothelial cells (ECs) lining the vessel walls, thus, causing dysfunction of the neurovascular unit (NVU), a complex multicellular system surrounding brain vessels. The NVU is extremely important for blood flow regulation, amyloid and tau clearance, and proper brain function, however, the mechanisms responsible for the effects of tau on ECs remain understudied. We hypothesize that protofibrillar tau mediates pro‐inflammatory EC activation tied to bioenergetic alterations, culminating in loss of barrier function. Method: Immortalized (D3) and primary (hCECs) human brain microvascular ECs were challenged with protofibrillar 1N4R tau. Trans‐endothelial electrical resistance (TEER) was measured by the ECIS Zθ system as an in‐vitro model of the BBB. Cytokine production was assessed using a V‐Plex Neuroinflammatory Panel 1 (MSD). IL‐4 release was determined in cell supernatant. Immunocytochemical analysis of junction protein (ZO‐1 and VE‐Cadherin) expression and western blotting for EC activation markers (VCAM‐1 and ICAM‐1) and junction proteins was performed. EC bioenergetics were measured by Seahorse Extracellular Flux Analyzer and EC death was determined, as well as caspase activation. Result: Reduced TEER was observed with protofibrillar tau, independently of EC death. VCAM‐1 expression significantly increased, whereas junction protein expression was decreased. Aggregated tau caused an increase in glycolysis at 24h, which reverted at further timepoints, whereas mitochondrial ATP production increased. IL‐4 production was increased at 24 hours, with similar trends at earlier timepoints. Blocking IL‐4 activity partially rescued TEER and decreased VCAM‐1 expression. Conclusion: Our results suggest that tau protofibrils mediate pro‐inflammatory EC activation, coupled with metabolic alterations. These molecular changes can contribute to loss of barrier integrity, exacerbating cerebrovascular dysfunction. [ABSTRACT FROM AUTHOR]

Background: Over the years, Alzheimer's Disease (AD) has been identified as a multifactorial disease, with cerebral vascular dysfunction being one of the most common and early pathological features. Vascular risk factors (VRF) are thought to further increase AD risk and pathology. Cerebral Amyloid Angiopathy (CAA) is defined as the accumulation of amyloid‐beta (Aβ) on the vascular wall. CAA occurs progressively with age in human AD brains, vascular dementias, and the Tg2576 AD mouse model. The Tg2576 develops significant amounts of parenchymal Aβ plaques and vascular amyloid deposits making it a valuable model to study CAA and AD. To study the contribution of VRF to CAA and AD pathology, we induced hyperhomocysteinemia (HHcy) and hypertension (HP) in Tg2576 mice. We have shown that carbonic anhydrase inhibitors (CAi) decreased vascular amyloid accumulation and neuroinflammation and prevented cognitive impairment in TgSwDI mice. Here, we evaluated the effects of HP and HHcy in AD and CAA pathology. In addition, we assessed the beneficial effects of CAi in the Tg2576 with/without the presence of VRF. Methods: To induce VRF, male and female WT and Tg2576 mice were fed a HHcy inducing diet and/or were given L‐NAME (NO inhibitor to induce HP) in the water starting at 5 months of age. To test the effects of CAi, the FDA‐approved CAi (Acetazolamide) was added to the diet starting at 5 months of age. Animals were then tested in a battery of behavioral measures including spatial learning and memory (barnes maze, fear conditioning, novel object recognition, open field, and rotarod), at 12 months of age. Result: The presence of HHcy or HT worsens spatial learning and memory in the WT and Tg2576 mice. Preliminary results may suggest that treatment with CAi improved spatial learning and memory in the WT and Tg2576 mice, in the presence or absence of VRFs. Conclusion: Taken together, our results suggest that VRF affect learning and memory in AD/CAA and non‐AD/CAA animal models. Importantly, we demonstrate that CAi is a promising treatment for treating mixed AD and CAA pathology. [ABSTRACT FROM AUTHOR]

Background: Recent evidence suggests that cerebrovascular dysfunction may precede and contribute to amyloid beta‐(Aβ)‐mediated pathology in Alzheimer's Disease (AD), particularly promoting endothelial cell damage and stress, causing the cerebral blood flow impairments, cerebral hypoperfusion, and blood brain barrier (BBB) permeability that are pathologically characteristic in AD. Studies have emerged suggesting a link between cardiovascular diseases and AD pathology, showing that cerebrovascular/cardiovascular risk factors (CVRFs), including hyperhomocysteinemia (Hhcy) and hypertension (HTN), and the cerebral consequences of these CVRFs, such as cerebral hypoperfusion, contribute to AD pathology and risk. Despite this, the underlying molecular mechanisms for these associations remain unclear. Previously, our lab has demonstrated that combined exposure of human cerebral microvascular endothelial cells (HCMECs) to Aβ40‐Q22 (vasculotropic Dutch mutant) and homocysteine resulted in potentiated increases in apoptosis and decreases in barrier integrity and angiogenic capabilities. Additionally, we have demonstrated that Aβ in combination with oxygen glucose deprivation exacerbates HCMEC cell death, barrier dysfunction, and angiogenic impairment. We tested the hypothesis that Tg2576 AD mice with hyperhomocysteinemia and/or hypertension will demonstrate exacerbated vascular cell death, BBB dysfunction, angiogenic defects and worsened AD pathology. Method: WT and Tg2576 AD mice (Swedish APP mutation) were fed with a hyperhomocysteinemia‐inducing diet, HTN‐inducing water (L‐NAME), or both starting at 5 months. Mice were sacrificed at 13‐14 months and tissue was harvested. Apoptotic mediator expression and vascular caspase‐3 activation were measured to assess apoptosis. BBB‐associated tight junction protein expression, GFAP/IBA1 expression and morphology (neuroinflammation), and microhemorrhages were measured to assess BBB integrity. Angiogenic mediator expression and CD31+ microvessel density were utilized to measure cerebral angiogenesis. Soluble and insoluble Aβ42 and Aβ40 were measured to assess AD pathology progression. Result: Tg2576 mice with CVRFs revealed exacerbated cerebral caspase‐3 activation and apoptosis as well as potentiated BBB and angiogenesis impairment versus WT mice and Tg2576 mice without CVRFs. Additionally, Tg2576 CVRF mice trended towards potentiated increases in cerebral soluble Aβ40 and fibrillar Aβ42. Conclusion: CVRFs potentiate increases in specific cerebrovascular and angiogenic deficits in Tg2576 mice. This study revealed new molecular mechanisms and druggable targets through which amyloidosis, Hhcy and HTN additively act to produce vascular damage and dysfunction in AD. [ABSTRACT FROM AUTHOR]

Background: FDA‐approved carbonic anhydrase inhibitors (CAIs) have been shown to attenuate Aβ pathology, neurodegeneration, and cerebrovascular dysfunction in models of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), suggesting a key role for CAs as a novel and previously unexplored target for AD therapy. Amyloid β accumulation severely impairs the cerebral neuro‐signaling pathway with a progressive loss in neurotrophic factors (NTFs, i.e., NGF and BDNF), potentially also affecting the cardiac nervous system and culminating in lethal heart dysfunction. Yet, no studies have proposed the use of CAIs for treating and preventing the systemic and cardiac effects of amyloidosis and AD. Methods: Here, we explored for the first time, the protective effects of a chronic CAIs therapeutic regimen against cardiac amyloid pathology, neuronal fibers' loss, and heart neurotrophic dysregulation in Tg2576 mice, a widely used model of AD and cerebral amyloidosis. Results: Cardiac fibrosis enhancement along with progressive Aβ deposition in the heart seriously affected the cardiac neuro‐signaling pathway culminating in a robust decline of BDNF expression associated with myocardial adrenergic nerve fibers and regenerated nerve endings impoverishment (stained with TH and GAP‐43 respectively) in 12‐month‐old Tg2576 mice compared to age‐matched WT littermates. These degenerative mechanisms severely compromised heart function, evidenced by a decline of both ejection fraction and fraction shortening percentage in Tg2576 animals. Accordingly, we observed that human Aβ40 or Aβ42 oligomers' treatment drastically reduced BDNF and GAP‐43 expression in human neuronal cells and human cardiomyocytes. Notably, long‐term CAIs treatment in Tg2576 mice reduced Aβ accumulation in the heart tissue and reverted cardiac neuro‐signaling pathway adverse remodeling, thus ameliorating heart function, as evidenced through echocardiographic analysis. These in vivo results were validated by in vitro experiments both in neuronal and cardiac cells. Conclusion: These findings suggest a new beneficial role of CAIs in preventing the Aβ‐induced cardiovascular remodeling and neuro‐signaling deregulation for the first time in the Tg2576 model of AD. Taken together with the positive effects of CAIs on cerebrovascular function and cognition, this study paves the way for future clinical trials aimed at repurposing FDA‐approved CAIs to prevent and correct both central and peripheral pathologies induced by AD and amyloidosis. [ABSTRACT FROM AUTHOR]

Background: Brain endothelial cell (EC) stress, including that induced by vascular amyloid β (Aβ) deposits in cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), contributes to cerebral blood flow impairment, blood brain barrier (BBB) damage, neurovascular unit dysfunction, microhemorrhages and hypoperfusion, precipitating neurodegeneration and neuroinflammation processes. Epidemiological and experimental evidence suggests that hyperhomocysteinemia (Hhcy) contributes to increasing AD risk as well as CAA pathology. However, the cellular and molecular mechanisms through which Aβ and Hhcy drive EC and BBB dysfunction, whether the molecular effects of these challenges are additive or independent, and possible therapeutic strategies, remain to be determined. Methods: Our work analyzed specific mitochondria‐ and death receptor‐mediated pathways in human cerebral microvascular ECs challenged with Aβ, high Hcy, or their combination. We also assessed the effects of these challenges, alone or combined, on the loss of BBB Resistance, junction proteins expression and structure and angiogenic activity, as well as the potential protective effects of carbonic anhydrase inhibitors. Results: Our data demonstrates that Aβ activates death receptors 4/5 (DR4/5)‐ and mitochondria‐mediated apoptotic pathways in human cerebral microvascular ECs and promotes loss of mitochondrial respiratory function (OXPHOS). Hhcy potentiates the Aβ‐mediated activation of both the extrinsic and intrinsic mitochondria‐mediated apoptotic pathways, the loss EC barrier permeability, a deregulation of multiple junction proteins and the impairment in VEGF‐A/VEGF‐receptor signaling and angiogenic capabilities. However, Hhcy does not affect endothelial Aβ‐mediated OXPHOS impairment and metabolic defects. Carbonic anhydrase inhibitors successfully improve EC apoptotic outcomes and microvascular fitness both in vitro and in vivo. Conclusion: This data highlights new and specific molecular mechanisms that drive endothelial and BBB pathology in AD/CAA in the presence or absence of a comorbid cerebrovascular condition such as Hhcy. Moreover, we discovered a new potential therapeutic target, carbonic anhydrase, whose inhibition can revert the cerebrovascular effects of Aβ in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Background: An increasing number of experimental and clinical studies show a link between Alzheimer's disease and heart diseases such as heart failure, ischemic heart disease, and atrial fibrillation. However, the mechanisms underlying the potential role of amyloid-β (Aβ) in the pathogenesis of cardiac dysfunction in Alzheimer's disease remain unknown. We have recently shown the effects of Aβ1 - 40 and Aβ1 - 42 on cell viability and mitochondrial function in cardiomyocytes and coronary artery endothelial cells. Objective: In this study, we investigated the effects of Aβ1 - 40 and Aβ1 - 42 on the metabolism of cardiomyocytes and coronary artery endothelial cells. Methods: Gas chromatography-mass spectrometry was used to analyze metabolomic profiles of cardiomyocytes and coronary artery endothelial cells treated with Aβ1 - 40 and Aβ1 - 42. In addition, we determined mitochondrial respiration and lipid peroxidation in these cells. Results: We found that the metabolism of different amino acids was affected by Aβ1 - 42 in each cell type, whereas the fatty acid metabolism is consistently disrupted in both types of cells. Lipid peroxidation was significantly increased, whereas mitochondrial respiration was reduced in both cell types in response to Aβ1 - 42. Conclusion: This study revealed the disruptive effects of Aβ on lipid metabolism and mitochondria function in cardiac cells. [ABSTRACT FROM AUTHOR]

This review summarizes recent evidence on how mid‐life hypertension, hyperhomocysteinemia (HHcy) and blood pressure variability, as well as late‐life hypotension, exacerbate Alzheimer's disease (AD) and dementia risk. Intriguingly, HHcy also increases the risk for hypertension, revealing the importance of understanding the relationship between comorbid cardiovascular risk factors. Hypertension‐induced dementia presents more evidently in women, highlighting the relevance of sex differences in the impact of cardiovascular risk. We summarize each major antihypertensive drug class's effects on cognitive impairment and AD pathology, revealing how carbonic anhydrase inhibitors, diuretics modulating cerebral blood flow, have recently gained preclinical evidence as promising treatment against AD. We also report novel vascular biomarkers for AD and dementia risk, highlighting those associated with hypertension and HHcy. Importantly, we propose that future studies should consider hypertension and HHcy as potential contributors to cognitive impairment, and that uncovering the underlying molecular mechanisms and biomarkers would aid in the identification of preventive strategies. [ABSTRACT FROM AUTHOR]