BACKGROUND: Cerebrovascular dysfunction (CVD) is an early feature of Alzheimer's disease (AD), contributing to the pathology progression, and suggesting a strict association between CVD and neurodegeneration. The ...
BACKGROUND: Cerebrovascular dysfunction (CVD) is an early feature of Alzheimer's disease (AD), contributing to the pathology progression, and suggesting a strict association between CVD and neurodegeneration. The majority of AD cases present cerebral amyloid angiopathy (CAA), neuropathological feature characterized by abnormal vasculotropic deposition of amyloid beta, mainly Aβ40. Severe CAA is also induced by familial Aβ variants, such as the Dutch-Q22. Our previous in vitro studies demonstrated that brain vascular amyloidosis elicits mitochondrial dysregulation and caspase-mediated apoptosis, in cells composing the neurovascular unit, including neurons, endothelial, glial and smooth muscle cells. Additionally, we showed that acetazolamide (ATZ) and methazolamide (MTZ), FDA-approved carbonic anhydrase inhibitors (CAIs) which cross the blood-brain barrier (BBB), hamper these detrimental processes. Carbonic anhydrases (CAs) represent a family of metalloenzymes catalyzing the reversible hydration of carbon dioxide, and their inhibition improves cerebral blood flow, vasoreactivity and neuronal excitability, pointing to CAs as CVD targets in AD. METHOD: We employed Tg-SwDI mice (expressing human amyloid precursor protein, APP, carrying the Swedish, Dutch and Iowa mutations), which develop fibrillar amyloid burden, primarily in the cerebral microvasculature, starting at 6 months. We fed the animals (from 8 to 16 months of age) a CAI-diet, following which we performed behavioral analysis, and harvested the brains for both biochemical and immunohistochemical examination. RESULT: Compared to untreated Tg mice, ATZ- and MTZ-fed animals showed reduced cognitive impairment, along with decreased vascular Aβ overload and astrogliosis, main pathological hallmarks of the disease. Tg animals exhibited Aβ deposition in endothelial and glial cells, leading to cell-specific caspase-3 activation. Interestingly, CAI-diet reduced endothelial and astrocytic Aβ deposits, and Aβ-induced cas
Stress, encompassing psychological, physical, and physiological challenges, is an important factor affecting an individual's well-being and potentially leading to psychiatric, neurodegenerative, immune, and metabo...
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Stress, encompassing psychological, physical, and physiological challenges, is an important factor affecting an individual's well-being and potentially leading to psychiatric, neurodegenerative, immune, and metabolic disorders. However, not everyone exposed to stress develops these conditions, highlighting the concept of resilience. Resilience is a dynamic process categorized into four dimensions: pre-existing resilience capacity, ongoing resilience processes, post-stress resilience outcomes, and recovery from psychopathologies. These dimensions involve genomic, cellular, and systemic interactions influenced by genetic factors, early life experiences, adult life experiences in addition to community/environmental factors, and health behaviors. The biological response to stress encompasses endocrine, autonomic, immunological, and behavioral components, modulated by stressor characteristics and individual traits. Due to the limitations in studying stress and resilience in humans, translational models using rodents and cell cultures are essential. Rodent models include acute, chronic, and traumatic stress paradigms, aiding the study of stress-related behavioral and molecular outcomes. Additionally, early life stress models, such as prenatal stress and maternal separation, provide insights into developmental impacts. In this review, first, rodent models for lifelong stress exposure will be summarized considering their validity, advantages, and limitations. Subsequently, an overview of models designed to enhance resilience capacity and process in rodents, and later the behavioral models employed to study the outcomes of resilience will be given. Lastly, the focus will be shifted to cell culture and iPSCs models. Finally, future considerations focused on improving translational models used to study stress and resilience will be discussed. It is aimed to provide an overview of designs for translational stress and resilience models to access more effective translational biom
The canonical Wnt signaling is an essential pathway that regulates cellular proliferation, maturation, and differentiation during neurodevelopment and maintenance of adult tissue homeostasis. This pathway has been imp...
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With recent advancements in nanomedicine, there has been growing interest in developing drug delivery systems with multifunctional capabilities. In this study, we developed a novel dual drug delivery system by combini...
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