Kinin B2 receptor can play a neuroprotective role in Alzheimer's disease

Caetano, Ariadiny Lima; Dong-Creste, Karis Ester; Amaral, Fabio Agostini; Monteiro-Silva, Karla Cristina; Pesquero, João Bosco; Araújo, Magali; Montor, Wagner Ricardo; Viel, Tânia Araújo; Buck, Hudson Sousa

doi:10.1016/j.npep.2015.09.001

Cited by 15 publications

(18 citation statements)

References 57 publications

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“…In the same way, the treatment with lithium made no difference in the density of this protein. This phenomenon was observed earlier by our group [ 50 ] and others where no significant difference in synaptophysin western-blotting between APP23 mice and wild-type controls were verified at 3 and 25 months of age [ 51 ] and could be explained by the enlargement of synaptic size to compensate de decrease in synapse number [ 52 , 53 ]. Also, the abscense of synaptophysin decrease could be related to a recognized trophic effect of APP contributing to a compensatory mechanism preventing or delaying the synaptic loss in face of the neuronal loss [ 54 ].…”

Section: Resultssupporting

confidence: 72%

Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer's Disease

et al. 2015

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The use of lithium is well established in bipolar disorders and the benefits are being demonstrated in neurodegenerative disorders. Recently, our group showed that treatment with microdose lithium stabilized the cognitive deficits observed in Alzheimer’s disease (AD) patients. In order to verify the lithium microdose potential in preventing the disease development, the aim of this work was to verify the effects of chronic treatment with microdose lithium given before and after the appearance of symptoms in a mouse model of a disease similar to AD. Transgenic mice (Cg-Tg(PDGFB-APPSwInd)20Lms/2J) and their non-transgenic litter mate genetic controls were treated with lithium carbonate (1.2 mg/Kg/day in drinking water) for 16 or 8 months starting at two and ten months of age, respectively. Similar groups were treated with water. At the end of treatments, both lithium treated transgenic groups and non-transgenic mice showed no memory disruption, different from what was observed in the water treated transgenic group. Transgenic mice treated with lithium since two months of age showed decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in cortex, when compared to non-treated transgenic mice. It is suitable to conclude that these data support the use of microdose lithium in the prevention and treatment of Alzheimer’s disease, once the neurohistopathological characteristics of the disease were modified and the memory of transgenic animals was maintained.

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Section: Resultssupporting

confidence: 72%

Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer's Disease

et al. 2015

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“…4b). Increased bradykinin receptor densities have been found after chronic infusion of Aβ [161]. Bradykinin acts on smooth muscle contraction or relaxation and vasodilatation through activation of the bradykinin 2 receptor and release of endothelialderived nitric oxide [162].…”

Section: Dysregulated Haemostasismentioning

confidence: 99%

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Klohs

2019

Neurodegener Dis

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Background: Cerebrovascular disease is a common comorbidity in patients with Alzheimer's disease (AD). It is believed to contribute additively to the cognitive impairment and to lower the threshold for the development of dementia. However, accumulating evidence suggests that dysfunction of the cerebral vasculature and AD neuropathology interact in multiple ways. Vascular processes even proceed AD neuropathology, implicating a causal role in the etiology of AD. Thus, the review aims to provide an integrated view on vascular dysfunction in AD. Summary: In AD, the cerebral vasculature undergoes pronounced cellular, morphological and structural changes, which alters regulation of blood flow, vascular fluid dynamics and vessel integrity. Stiffening of central blood vessels lead to transmission of excessive pulsatile energy to the brain microvasculature, causing endorgan damage. Moreover, a dysregulated hemostasis and chronic vascular inflammation further impede vascular function, where its mediators interact synergistically. Changes of the cerebral vasculature are triggered and driven by systemic vascular abnormalities that are part of aging, and which can be accelerated and aggravated by cardiovascular diseas-es. Key Messages: In AD, the cerebral vasculature is the locus where multiple pathogenic processes converge and contribute to cognitive impairment. Understanding the molecular mechanism and pathophysiology of vascular dysfunction in AD and use of vascular blood-based and imaging biomarker in clinical studies may hold promise for future prevention and therapy of the disease.

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“…We also found increased densities of synapses and BKB2R in KOB1R animals infused with Aβ 1-40. Mice lacking B2R submitted to the same protocol, showed an increase in the number of amyloid plaques compared to the control [ 5 ], reinforcing the hypothesis that the B2R has a neuroprotective role. Moreover, we also demonstrated that the chronic infusion of amyloid-β peptide led to an increase in the density of B1R and B2R in brain regions associated with cognitive processes, as well as an increase in BK concentration in cerebrospinal fluid, suggesting the involvement of KKS activation in AD [ 6 , 15 ].…”

Section: Discussionmentioning

confidence: 68%

“…No disease modifying therapy has yet been found for the treatment of AD patients, although our group has previously shown that microdose lithium treatment can prevent and stabilize AD-related symptoms [ 2 ] but without any regression of the disease. Other research from our group has shown the involvement of kinin receptors in aging and Alzheimer’s disease [ 3 , 4 , 5 ]. Kinins act on two receptors, B1 and B2, coupled to different G proteins.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, chronic infusion of Aβ peptide in BKB2R knockout mice leads to premature memory impairment when compared to wild-type animals, as well as an increased number of Aβ plaques. However, memory impairment was absent in BKB1R knockout mice infused with Aβ peptide, with an increase in BKB2R density in memory processing-related areas, suggesting a neuroprotective role for BKB2R [ 3 , 4 , 5 ]. In recent years, several studies suggested the inhibition or activation of B1 and B2 receptors as therapeutic targets for different brain disorders such as ischemic stroke, temporal lobe epilepsy, febrile illness, spinal cord injury, traumatic brain injury, and in Alzheimer’s disease with controversial results [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Kinin B2 Receptor Activation Prevents the Evolution of Alzheimer’s Disease Pathological Characteristics in a Transgenic Mouse Model

et al. 2020

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Background: Alzheimer’s disease is mainly characterized by remarkable neurodegeneration in brain areas related to memory formation. This progressive neurodegeneration causes cognitive impairment, changes in behavior, functional disability, and even death. Our group has demonstrated changes in the kallikrein–kinin system (KKS) in Alzheimer’s disease (AD) experimental models, but there is a lack of evidence about the role of the KKS in Alzheimer’s disease. Aim: In order to answer this question, we evaluated the potential of the kinin B2 receptors (BKB2R) to modify AD characteristics, particularly memory impairment, neurodegeneration, and Aβ peptide deposition. Methods: To assess the effects of B2, we used transgenic Alzheimer’s disease mice treated with B2 receptor (B2R) agonists and antagonists, and performed behavioral and biochemical tests. In addition, we performed organotypic hippocampal culture of wild-type (WT) and transgenic (TG) animals, where the density of cytokines, neurotrophin BDNF, activated astrocyte marker S100B, and cell death were analyzed after treatments. Results: Treatment with the B2R agonist preserved the spatial memory of transgenic mice and decreased amyloid plaque deposition. In organotypic hippocampal culture, treatment with B2R agonist decreased cell death, neuroinflammation, and S100B levels, and increased BDNF release. Conclusions: Our results indicate that the kallikrein–kinin system plays a beneficial role in Alzheimer’s disease through B2R activation. The use of B2R agonists could, therefore, be a possible therapeutic option for patients diagnosed with Alzheimer’s disease.

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Kinin B2 receptor can play a neuroprotective role in Alzheimer's disease

Cited by 15 publications

References 57 publications

Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer's Disease

Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer's Disease

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Kinin B2 Receptor Activation Prevents the Evolution of Alzheimer’s Disease Pathological Characteristics in a Transgenic Mouse Model

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