Evaluation of BR1 and BI30 AAVs for Brain Endothelial Tropism.

Brain endothelial cells are critical for homeostasis of the central nervous system. Novel adeno-associated viruses (AAV) with brain endothelial cell tropism have been developed and are beginning to be employed in mechanistic and therapeutic research. Studies using AAVs can be involved in terms of cost, time and personnel, and many groups, including our own, are not experts on the technology.

Loss of Endothelial Dysregulates Neural Function In Vivo.

Background: We recently found that loss of endothelial cell disrupts neurovascular and synaptic function. However, whether endothelial is detrimental or protective for neural function under physiological conditions is unknown. Therefore, the goal of this study was to determine the role of endothelial cell in regulating brain function in vivo.

Apolipoprotein E polymorphisms and female fertility in a transgenic mouse model of Alzheimer's disease.

Apolipoprotein E (APOE) is a major cholesterol carrier responsible for lipid transport and injury repair in the brain. The human APOE gene (h-APOE) has 3 naturally occurring alleles: ε3, the common allele; ε4, which increases Alzheimer's disease (AD) risk up to 15-fold; and ε2, the rare allele which protects against AD. Although APOE4 has negative effects on neurocognition in old age, its persistence in the population suggests a survival advantage.

Estradiol improves behavior in FAD transgenic mice that express but not after ovariectomy.

Increasing evidence suggests that female individuals have a higher Alzheimer's disease (AD) risk associated with post-menopausal loss of circulating estradiol (E). However, clinical data are conflicting on whether E lowers AD risk. One potential contributing factor is .

Induced saturation transfer recovery steady states (iSTRESS) for proton exchange rate mapping with CEST MRI, a preliminary study.

Proton exchange underpins essential mechanisms in diverse MR imaging contrasts. Omega plots have proven effective in mapping proton exchange rates (k) in live human brains, enabling the differentiation of MS lesion activities and characterization of ischemic stroke. However, Omega plots require extended saturation durations (typically 5 to 10 s), resulting in high specific absorption rates (SAR) that can hinder clinical feasibility.

Caveolin-1 mediates blood-brain barrier permeability, neuroinflammation, and cognitive impairment in SARS-CoV-2 infection.

Blood-brain barrier (BBB) permeability can cause neuroinflammation and cognitive impairment. Caveolin-1 (Cav-1) critically regulates BBB permeability, but its influence on the BBB and consequent neurological outcomes in respiratory viral infections is unknown. We used Cav-1-deficient mice with genetically encoded fluorescent endothelial tight junctions to determine how Cav-1 influences BBB permeability, neuroinflammation, and cognitive impairment following respiratory infection with mouse adapted (MA10) SARS-CoV-2 as a model for COVID-19.

Engineered Wnt7a ligands rescue blood-brain barrier and cognitive deficits in a COVID-19 mouse model.

Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating cerebrovascular dysfunction and inflammation following mild respiratory SARS-CoV-2 infection. To this end, we performed unbiased transcriptional analysis to identify brain endothelial cell signalling pathways dysregulated by mouse adapted SARS-CoV-2 MA10 in aged immunocompetent C57Bl/6 mice in vivo.

APOE2 Heterozygosity Reduces Hippocampal Soluble Amyloid-β42 Levels in Non-Hyperlipidemic Mice.

APOE2 lowers Alzheimer's disease (AD) risk; unfortunately, the mechanism remains poorly understood and the use of mice models is problematic as APOE2 homozygosity is associated with hyperlipidemia. In this study, we developed mice that are heterozygous for APOE2 and APOE3 or APOE4 and overexpress amyloid-β peptide (Aβ) (EFAD) to evaluate the effect of APOE2 dosage on Aβ pathology. We found that heterozygous mice do not exhibit hyperlipidemia.

A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3.

Background: Alzheimer's disease (AD) is characterized by cognitive dysfunction and amyloid plaques composed of the amyloid-beta peptide (Aβ). APOE is the greatest genetic risk for AD with APOE4 increasing risk up to ~ 15-fold compared to APOE3. Evidence suggests that levels and lipidation of the apoE protein could regulate AD progression.

genotype and sex modulate Alzheimer's disease pathology in aged EFAD transgenic mice.

Increasing evidence supports that age, and sex interact to modulate Alzheimer's disease (AD) risk, however the underlying pathways are unclear. One way that AD risk factors may modulate cognition is by impacting amyloid beta (Aβ) accumulation as plaques, and/or neuroinflammation Therefore, the goal of the present study was to evaluate the extent to which age, and sex modulate Aβ pathology, neuroinflammation and behavior . To achieve this goal, we utilized the EFAD mice, which express human or and have five familial AD mutations (FAD) that result in Aβ42 overproduction.

A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice.

Background: APOE genotype is the greatest genetic risk factor for sporadic Alzheimer's disease (AD). APOE4 increases AD risk up to 12-fold compared to APOE3, an effect that is greater in females. Evidence suggests that one-way APOE could modulate AD risk and progression through neuroinflammation.

Endothelial Cell Regulates Neurovascular, Neuronal, and Behavioral Function.

Background: Specialized brain endothelial cells and human are independently important for neurovascular function, yet whether expression by endothelial cells contributes to brain function is currently unknown. In the present study, we determined whether the loss of endothelial cell impacts brain vascular and neural function.

Methods: We developed /Cdh5(PAC)-CreERT2 () and /Cdh5(PAC)-CreERT2 (, control) mice and induced endothelial cell knockdown with tamoxifen at ≈4 to 5 weeks of age.

Higher Neuronal Facilitation and Potentiation with APOE4 Suppressed by Angiotensin II.

Progressive hippocampal degeneration is a key component of Alzheimer's disease (AD) progression. Therefore, identifying how hippocampal neuronal function is modulated early in AD is an important approach to eventually prevent degeneration. AD-risk factors and signaling molecules likely modulate neuronal function, including APOE genotype and angiotensin II.

Higher Neuronal Facilitation and Potentiation with APOE4 Suppressed by Angiotensin II.

Progressive hippocampal degeneration is a key component of Alzheimer's disease (AD) progression. Therefore, identifying how hippocampal neuronal function is modulated early in AD is an important approach to eventually prevent degeneration. AD-risk factors and signaling molecules likely modulate neuronal function, including genotype and angiotensin II.

CRISPR-Cas9 Knock-In of T513M and G41S Mutations in the Murine β-Galactosyl-Ceramidase Gene Re-capitulates Early-Onset and Adult-Onset Forms of Krabbe Disease.

Krabbe Disease (KD) is a lysosomal storage disorder characterized by the genetic deficiency of the lysosomal enzyme β-galactosyl-ceramidase (GALC). Deficit or a reduction in the activity of the GALC enzyme has been correlated with the progressive accumulation of the sphingolipid metabolite psychosine, which leads to local disruption in lipid raft architecture, diffuse demyelination, astrogliosis, and globoid cell formation. The mouse, the most used animal model, has a nonsense mutation, which limits the study of how different mutations impact the processing and activity of GALC enzyme.

LPC-DHA/EPA-Enriched Diets Increase Brain DHA and Modulate Behavior in Mice That Express Human .

Compared with , is associated with greater age-related cognitive decline and higher risk of neurodegenerative disorders. Therefore, development of supplements that target genotype-modulated processes could provide a great benefit for the aging population. Evidence suggests a link between genotype and docosahexaenoic acid (DHA); however, clinical studies with current DHA supplements have produced negative results in dementia.

Autocrine Effects of Brain Endothelial Cell-Produced Human Apolipoprotein E on Metabolism and Inflammation .

Reports of -associated neurovascular dysfunction during aging and in neurodegenerative disorders has led to ongoing research to identify underlying mechanisms. In this study, we focused on whether the genotype of brain endothelial cells modulates their own phenotype. We utilized a modified primary mouse brain endothelial cell isolation protocol that enabled us to perform experiments without subculture.

Stiffness of aortic arch and carotid arteries increases in -knockout mice with high-fat diet: evidence from echocardiography.

Arterial stiffness is an effective predictor of atherosclerosis. Measurement of pulse-wave velocity (PWV) is a gold-standard approach to study arterial stiffness. This study aims to examine arterial stiffness and heart functions via echocardiography at an early stage of atherosclerosis.

Promotes Tonic-Clonic Seizures, an Effect Modified by Familial Alzheimer's Disease Mutations.

Seizures are emerging as a common symptom in Alzheimer's disease (AD) patients, often attributed to high levels of amyloid β (Aβ). However, the extent that AD disease risk factors modulate seizure activity in aging and AD-relevant contexts is unclear. is the greatest genetic risk factor for AD and has been linked to seizures independent of AD and Aβ.

Systemic Candesartan Treatment Modulates Behavior, Synaptic Protein Levels, and Neuroinflammation in Female Mice That Express Human .

Evidence suggests that angiotensin receptor blockers (ARBs) could be beneficial for Alzheimer's disease (AD) patients independent of any effects on hypertension. However, studies in rodent models directly testing the activity of ARB treatment on behavior and AD-relevent pathology including neuroinflammation, Aβ levels, and cerebrovascular function, have produced mixed results. is a major genetic risk factor for AD and has been linked to many of the same functions as those purported to be modulated by ARB treatment.

Extending the Calpain-Cathepsin Hypothesis to the Neurovasculature: Protection of Brain Endothelial Cells and Mice from Neurotrauma.

The calpain-cathepsin hypothesis posits a key role for elevated calpain-1 and cathepsin-B activity in the neurodegeneration underlying neurotrauma and multiple disorders including Alzheimer's disease (AD). AD clinical trials were recently halted on alicapistat, a selective calpain-1 inhibitor, because of insufficient exposure of neurons to the drug. In contrast to neuroprotection, the ability of calpain-1 and cathepsin-B inhibitors to protect the blood-brain barrier (BBB), is understudied.

Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease.

Neonatal AAV9-gene therapy of the lysosomal enzyme galactosylceramidase (GALC) significantly ameliorates central and peripheral neuropathology, prolongs survival, and largely normalizes motor deficits in Twitcher mice. Despite these therapeutic milestones, new observations identified the presence of multiple small focal demyelinating areas in the brain after 6-8 months. These lesions are in stark contrast to the diffuse, global demyelination that affects the brain of naive Twitcher mice.

Relevance of transgenic mouse models for Alzheimer's disease.

Over the last several decades, a number of mouse models have been generated for mechanistic and preclinical therapeutic research on Alzheimer's disease (AD)-like behavioral impairments and pathology. Acceptance or rejection of these models by the scientific community is playing a prominent role in how research findings are viewed and whether grants get funded and manuscripts published. The question of whether models are useful has become an exceptionally contentious issue.

Epidermal growth factor treatment of female mice that express at an age of advanced pathology mitigates behavioral and cerebrovascular dysfunction.

is a major genetic risk factor for Alzheimer's disease and high amyloid-β (Aβ) levels in the brain are a pathological hallmark of the disease. However, the contribution of specific -modulated Aβ-dependent and Aβ-independent functions to cognitive decline remain unclear. Increasing evidence supports a role of in modulating cerebrovascular function, however whether ameliorating this dysfunction can improve behavioral function is still under debate.