CDK5 Targeting as a Therapy for Recovering Neurovascular Unit Integrity in Alzheimer’s Disease

2020 ◽  
pp. 1-21
Author(s):  
Rafael Andrés Posada-Duque ◽  
Gloria Patricia Cardona-Gómez
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurovascular Unit ◽  
Cellular Adhesion ◽  
Chronic Injury ◽  
Intermediary Cell ◽  
Cell Components ◽  
Protective Strategies ◽  
The Individual ◽  
The Brain

The neurovascular unit (NVU) is responsible for synchronizing the energetic demand, vasodynamic changes, and neurochemical and electrical function of the brain through a closed and interdependent interaction of cell components conforming to brain tissue. In this review, we will focus on cyclin-dependent kinase 5 (CDK5) as a molecular pivot, which plays a crucial role in the healthy function of neurons, astrocytes, and the endothelium and is implicated in the cross-talk of cellular adhesion signaling, ion transmission, and cytoskeletal remodeling, thus allowing the individual and interconnected homeostasis of cerebral parenchyma. Then, we discuss how CDK5 overactivation affects the integrity of the NVU in Alzheimer’s disease (AD) and cognitive impairment; we emphasize how CDK5 is involved in the excitotoxicity spreading of glutamate and Ca2+ imbalance under acute and chronic injury. Additionally, we present pharmacological and gene therapy strategies for producing partial depletion of CDK5 activity on neurons, astrocytes, or endothelium to recover neuroplasticity and neurotransmission, suggesting that the NVU should be the targeted tissue unit in protective strategies. Finally, we conclude that CDK5 could be effective due to its intervention on astrocytes by its end feet on the endothelium and neurons, acting as an intermediary cell between systemic and central communication in the brain. This review provides integrated guidance regarding the pathogenesis of and potential repair strategies for AD.

scholarly journals Impact of Tau on Neurovascular Pathology in Alzheimer's Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Elisa Canepa ◽  
Silvia Fossati
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Neurovascular Unit ◽  
Amyloid Angiopathy ◽  
Brain Vasculature ◽  
Mitochondrial Alterations ◽  
Species Production ◽  
The Impact ◽  
The Brain

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most prevalent cause of dementia. The main cerebral histological hallmarks are represented by parenchymal insoluble deposits of amyloid beta (Aβ plaques) and neurofibrillary tangles (NFT), intracellular filamentous inclusions of tau, a microtubule-associated protein. It is well-established that cerebrovascular dysfunction is an early feature of AD pathology, but the detrimental mechanisms leading to blood vessel impairment and the associated neurovascular deregulation are not fully understood. In 90% of AD cases, Aβ deposition around the brain vasculature, known as cerebral amyloid angiopathy (CAA), alters blood brain barrier (BBB) essential functions. While the effects of vascular Aβ accumulation are better documented, the scientific community has only recently started to consider the impact of tau on neurovascular pathology in AD. Emerging compelling evidence points to transmission of neuronal tau to different brain cells, including astrocytes, as well as to the release of tau into brain interstitial fluids, which may lead to perivascular neurofibrillar tau accumulation and toxicity, affecting vessel architecture, cerebral blood flow (CBF), and vascular permeability. BBB integrity and functionality may therefore be impacted by pathological tau, consequentially accelerating the progression of the disease. Tau aggregates have also been shown to induce mitochondrial damage: it is known that tau impairs mitochondrial localization, distribution and dynamics, alters ATP and reactive oxygen species production, and compromises oxidative phosphorylation systems. In light of this previous knowledge, we postulate that tau can initiate neurovascular pathology in AD through mitochondrial dysregulation. In this review, we will explore the literature investigating tau pathology contribution to the malfunction of the brain vasculature and neurovascular unit, and its association with mitochondrial alterations and caspase activation, in cellular, animal, and human studies of AD and tauopathies.

scholarly journals Influencia del estrés en la Enfermedad de Alzheimer. // Stress influence in Alzheimer’s disease

Ciencia Unemi ◽  
2018 ◽  
Vol 10 (25) ◽  
pp. 123
Author(s):  
Maria Alejandra Vallejo-Johnson ◽  
Patricia Marcial-Velastegui
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Damage ◽  
The Body ◽  
Daily Routine ◽  
Stressful Situation ◽  
The Individual ◽  
Stress Influences ◽  
The Brain

Existen diversos estudios que proponen las causas de la Enfermedad de Alzheimer (EA), las cuales pueden ser: biológicas, genéticas, cronológicas y ambientales, dentro de ésta última se encuentra el estrés como una influencia para el inicio de dicha patología. Según las distintas teorías del estrés, el sujeto, al encontrarse frente a una situación estresante, sufre diversos cambios en su cuerpo para sobrellevar dicho acontecimiento. El cerebro es el encargado de poner al cuerpo en alerta y en marcha para actuar frente a dicho cambio. El estrés prolongado conlleva a alteraciones en las vías cerebrales, específicamente un daño neuronal del hipocampo, el cual es el encargado de los recuerdos y memoria. Éste al verse afectado, repercute en la memoria del sujeto y por lo tanto empieza a fallar; el sujeto se ve en la incapacidad para recordar y realizar distintas actividades rutinarias. Mediante la investigación documental y encuestas a profesionales de la salud, se obtuvo información tanto del estrés como de la Enfermedad de Alzheimer para luego concluir en la influencia del mismo en el origen de la enfermedad. Se concluye que el estrés perenne repercute en la muerte de neuronas del hipocampo lo que conlleva a la EA. AbstractThere are different studies that propose that the causes of Alzheimer might be biological, genetic, chronological and environmental. Within the environmental aspects, the stress influences the beginning of this pathology. There are several studies that propose the causes of Alzheimer's disease (AD), which can be: biological, genetic, chronological and environmental, within the latter is the stress that influences the beginning of this pathology. According to different theories of stress, the individual, while facing a stressful situation, experiences many changes in the body in order to deal with this situation. The brain is in charge of alerting the body to protect itself against that change. The long-term stress alters the brain pathways, producing specifically a neuronal damage in the hippocampus that is responsible for memories and memory. This affects memory and therefore individual begins to fail, and then, the person cannot remember how to do the daily routine. Through bibliographical research and surveys applied to healthcare professionals, information was obtained on both stress and Alzheimer's disease to establish the influence of that condition on the disease. The study concludes that long-term stress affects the death of neurons in the hippocampus, which leads to AD.

scholarly journals 326 Whey proteins for prevention and intervention in Alzheimer’s Disease

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 68-69
Author(s):  
Louise E Bennett
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Whey Proteins ◽  
Memory Loss ◽  
Aβ Peptides ◽  
Over Expression ◽  
Potential Benefits ◽  
Individual Potential ◽  
The Individual ◽  
The Brain

Abstract Alzheimer’s disease, resulting from the over-expression of amyloid precursor protein (APP) and accumulation of plaques comprising the APP-derived amyloid beta (Aβ), is a diagnostic and pathological brain feature of Alzheimer’s disease (AD). For older, predisposed people, accumulation of Aβ plaque in the brain precedes symptoms of memory loss by decades. There is a growing consensus that over-expression of APP may also reflect a defense response against infection, via the antibiotic effects of Aβ, which becomes toxic when Aβ peptides cannot be cleared from the brain. These scenarios permit two possible pathways of potential intervention from whey proteins mediated by lactoferrin and hydrolyzed whey proteins. In particular, the interference of fibril assembly whey-derived peptides can promote opportunity for clearance of aggregating forms of Aβ, while the anti-microbial activity of whey proteins such as lactoferrin have potential to suppress the activity of microbes (and viruses) and collectively manage the progress of AD. This presentation will explain the individual potential benefits of whey peptides and lactoferrin, based on available evidence. More research is required to determine if a synergistic effect might be possible from this therapeutic combination.

scholarly journals The Neurovascular Unit Dysfunction in Alzheimer’s Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 2022 ◽  
Author(s):  
Luis O. Soto-Rojas ◽  
Mar Pacheco-Herrero ◽  
Paola A. Martínez-Gómez ◽  
B. Berenice Campa-Córdoba ◽  
Ricardo Apátiga-Pérez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurovascular Unit ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Amyloid Angiopathy ◽  
Amyloid Β Peptide ◽  
Vascular Risk ◽  
Therapeutic Approaches ◽  
The Brain

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid β peptide (Aβ) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aβ clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aβ. An increase in Aβ amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aβ or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.

scholarly journals Dissecting Sex-Related Cognition between Alzheimer’s Disease and Diabetes: From Molecular Mechanisms to Potential Therapeutic Strategies

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Ghulam Md Ashraf ◽  
Mahmoud Ahmed Ebada ◽  
Mohd Suhail ◽  
Ashraf Ali ◽  
Md. Sahab Uddin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Sexually Dimorphic ◽  
Metabolic Complications ◽  
Male And Female ◽  
Precise Diagnosis ◽  
Protective Strategies ◽  
The Brain

The brain is a sexually dimorphic organ that implies different functions and structures depending on sex. Current pharmacological approaches against different neurological diseases act distinctly in male and female brains. In all neurodegenerative diseases, including Alzheimer’s disease (AD), sex-related outcomes regarding pathogenesis, prevalence, and response to treatments indicate that sex differences are important for precise diagnosis and therapeutic strategy. Pathogenesis of AD includes vascular dementia, and in most cases, this is accompanied by metabolic complications with similar features as those assembled in diabetes. This review discusses how AD-associated dementia and diabetes affect cognition in relation to sex difference, as both diseases share similar pathological mechanisms. We highlight potential protective strategies to mitigate amyloid-beta (Aβ) pathogenesis, emphasizing how these drugs act in the male and female brains.

scholarly journals Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains

2021 ◽  
Vol 22 (7) ◽  
pp. 3654
Author(s):  
Luis O. Soto-Rojas ◽  
B. Berenice Campa-Córdoba ◽  
Charles R. Harrington ◽  
Andrés Salas-Casas ◽  
Mario Hernandes-Alejandro ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurovascular Unit ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Amyloid Β Peptide ◽  
Cerebral Blood Vessels ◽  
Amyloid Deposits ◽  
Cellular Components ◽  
The Brain

Alzheimer’s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood–brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immunofluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aβ in AD.

scholarly journals Interactions between Amyloid-Β Proteins and Human Brain Pericytes: Implications for the Pathobiology of Alzheimer’s Disease

2020 ◽  
Vol 9 (5) ◽  
pp. 1490 ◽  
Author(s):  
Donald J. Alcendor
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurovascular Unit ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Blood Retinal Barrier ◽  
Endothelin 1 ◽  
Brain Pericytes ◽  
Aging Populations ◽  
The Brain

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia, especially among aging populations. Despite advances in AD research, the underlying cause and the discovery of disease-modifying treatments have remained elusive. Two key features of AD pathology are the aberrant deposition of amyloid beta (amyloid-β or Aβ) proteins in the brain parenchyma and Aβ toxicity in brain pericytes of the neurovascular unit/blood–brain barrier (NVU/BBB). This toxicity induces oxidative stress in pericytes and leads to capillary constriction. The interaction between pericytes and Aβ proteins results in the release of endothelin-1 in the pericytes. Endothelin-1 interacts with ETA receptors to cause pericyte contraction. This pericyte-mediated constriction of brain capillaries can cause chronic hypoperfusion of the brain microvasculature, subsequently leading to the neurodegeneration and cognitive decline observed in AD patients. The interaction between Aβ proteins and brain pericytes is largely unknown and requires further investigation. This review provides an updated overview of the interaction between Aβ proteins with pericytes, one the most significant and often forgotten cellular components of the BBB and the inner blood–retinal barrier (IBRB). The IBRB has been shown to be a window into the central nervous system (CNS) that could allow the early diagnosis of AD pathology in the brain and the BBB using modern photonic imaging systems such as optical coherence tomography (OCT) and two-photon microscopy. In this review, I explore the regulation of Aβ proteins in the brain parenchyma, their role in AD pathobiology, and their association with pericyte function. This review discusses Aβ proteins and pericytes in the ocular compartment of AD patients as well as strategies to rescue or protect pericytes from the effects of Aβ proteins, or to replace them with healthy cells.

scholarly journals Dissecting the Crosstalk between Endothelial Mitochondrial Damage, Vascular Inflammation, and Neurodegeneration in Cerebral Amyloid Angiopathy and Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2903
Author(s):  
Rebecca M. Parodi-Rullán ◽  
Sabzali Javadov ◽  
Silvia Fossati
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Amyloid Angiopathy ◽  
Vascular Inflammation ◽  
Neurovascular Unit ◽  
Brain Parenchyma ◽  
Amyloid Angiopathy ◽  
Wide Range ◽  
Cerebral Amyloid ◽  
The Brain

Alzheimer’s disease (AD) is the most prevalent cause of dementia and is pathologically characterized by the presence of parenchymal senile plaques composed of amyloid β (Aβ) and intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein. The accumulation of Aβ also occurs within the cerebral vasculature in over 80% of AD patients and in non-demented individuals, a condition called cerebral amyloid angiopathy (CAA). The development of CAA is associated with neurovascular dysfunction, blood–brain barrier (BBB) leakage, and persistent vascular- and neuro-inflammation, eventually leading to neurodegeneration. Although pathologically AD and CAA are well characterized diseases, the chronology of molecular changes that lead to their development is still unclear. Substantial evidence demonstrates defects in mitochondrial function in various cells of the neurovascular unit as well as in the brain parenchyma during the early stages of AD and CAA. Dysfunctional mitochondria release danger-associated molecular patterns (DAMPs) that activate a wide range of inflammatory pathways. In this review, we gather evidence to postulate a crucial role of the mitochondria, specifically of cerebral endothelial cells, as sensors and initiators of Aβ-induced vascular inflammation. The activated vasculature recruits circulating immune cells into the brain parenchyma, leading to the development of neuroinflammation and neurodegeneration in AD and CAA.

scholarly journals Neuronal Glial Crosstalk: Specific and Shared Mechanisms in Alzheimer’s Disease

2022 ◽  
Vol 12 (1) ◽  
pp. 75
Author(s):  
Vishal Chavda ◽  
Kavita Singh ◽  
Vimal Patel ◽  
Meerambika Mishra ◽  
Awdhesh Kumar Mishra
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Glial Cells ◽  
Present Review ◽  
Cell Contact ◽  
Direct Cell ◽  
The Individual ◽  
The Brain ◽  
Supportive Cells

The human brain maintains billions of neurons functional across the lifespan of the individual. The glial, supportive cells of the brain are indispensable to neuron elasticity. They undergo various states (active, reactive, macrophage, primed, resting) and carefully impose either quick repair or the cleaning of injured neurons to avoid damage extension. Identifying the failure of these interactions involving the relation of the input of glial cells to the inception and/or progression of chronic neurodegenerative diseases (ND) is crucial in identifying therapeutic options, given the well-built neuro-immune module of these diseases. In the present review, we scrutinize different interactions and important factors including direct cell–cell contact, intervention by the CD200 system, various receptors present on their surfaces, CXC3RI and TREM2, and chemokines and cytokines with special reference to Alzheimer’s disease (AD). The present review of the available literature will elucidate the contribution of microglia and astrocytes to the pathophysiology of AD, thus evidencing glial cells as obligatory transducers of pathology and superlative targets for interference.

The role of perivascular innervation and neurally mediated vasoreactivity in the pathophysiology of Alzheimer's disease

2017 ◽  
Vol 131 (12) ◽  
pp. 1207-1214 ◽  
Author(s):  
Shereen Nizari ◽  
Ignacio A. Romero ◽  
Cheryl A. Hawkes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Tone ◽  
Neurovascular Unit ◽  
Efficient Removal ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Considerable Work ◽  
The Brain

Neuronal death is a hallmark of Alzheimer's disease (AD) and considerable work has been done to understand how the loss of interconnectivity between neurons contributes to the associated dementia. Often overlooked however, is how the loss of neuronal innervation of blood vessels, termed perivascular innervation, may also contribute to the pathogenesis of AD. There is now considerable evidence supporting a crucial role for the neurovascular unit (NVU) in mediating the clearance of the β-amyloid (Aβ) peptide, one of the main pathological constituents of AD, from the brain. Moreover, efficient removal appears to be dependent on the communication of cells within the NVU to maintain adequate vascular tone and pulsatility. This review summarizes the composition of the NVU, including the sources of perivascular innervation and how the NVU mediates Aβ clearance from the brain. It also explores evidence supporting the hypothesis that loss of neurally mediated vasoreactivity contributes to Aβ pathology in the AD brain.

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