The GRK2 Overexpression Is a Primary Hallmark of Mitochondrial Lesions during Early Alzheimer Disease

Increasing evidence points to vascular damage as an early contributor to the development of two leading causes of age-associated dementia, namely Alzheimer disease (AD) and AD-like pathology such as stroke. This review focuses on the role of G protein-coupled receptor kinases (GRKs) as they relate to dementia and how the cardio and cerebrovasculature is involved in AD pathogenesis. The exploration of GRKs in AD pathogenesis may help bridge gaps in our understanding of the heart-brain connection in relation to neurovisceral damage and vascular complications of AD. The a priori basis for this inquiry stems from the fact that kinases of this family regulate numerous receptor functions in the brain, myocardium and elsewhere. The aim of this review is to discuss the finding of GRK2 overexpression in the context of early AD pathogenesis. Also, we consider the consequences for this overexpression as a loss of G-protein coupled receptor (GPCR) regulation, as well as suggest a potential role for GPCRs and GRKs in a unifying theory of AD pathogenesis through the cerebrovasculature. Finally, we synthesize this newer information in an attempt to put it into context with GRKs as regulators of cellular function, which makes these proteins potential diagnostic and therapeutic targets for future pharmacological intervention

Immunocytochemical Characterization of Alzheimer’s Disease Hallmarks in APP/PS1 Transgenic Mice Treated with a New Anti-Amyloid-β Vaccine

Introduction: APP/PS1 double-transgenic mouse models of Alzheimer’s disease (AD), which overexpress mutated forms of the gene for the human amyloid precursor protein (APP) and presenilin 1 (PS1), have provided robust neuropathological hallmarks of an AD-like pattern at early ages. This study aimed to characterize immunocytochemical patterns of the AD mouse brain, which is treated with the EB101 vaccine, as a model for human AD.Material and methods: In this novel vaccine, a new approach has been taken to circumvent past failures with A? vaccines by judiciously selecting an adjuvant consisting of a physiological matrix embedded in liposomes, composed of naturally occurring phospholipids (phosphatidylcholine, phosphatidylglycerol, and cholesterol).Results: Our findings showed that the administration of amyloid-?1?42 (A?) and sphingosine-1-phosphate emulsified in liposome complex (EB101) to APP/PS1 mice before the onset of A? brain deposition (at 7 weeks of age) and/or at an older age (35 weeks of age) can be effective in both halting the progression and clearing the AD-like neuropathological hallmarks. In addition, passive immunization with EB101 did not activate inflammatory responses from the immune system and astrocytes. Consistent with a decreased inflammatory background, the basal immunological interaction between the T cells and the affected areas (hippocampus) in the brain of treated mice was notably reduced.Conclusion: These results provide strong evidence that immunization with the EB101 vaccine prevents and attenuates AD neuropathology in this type of double-transgenic mice

The role of oxidative stress in the pathogenesis of Alzheimer's disease

[ES]: La presencia de estrés oxidativo es la característica más temprana de la Enfermedad de Alzheimer (EA), lo cual proporciona un atractivo objetivo para intervenciones terapéuticas. Entre los mayores retos que se presentan actualmente están el establecimiento de la fuente de estrés oxidativo y la determinación de cómo este proceso puede influir en la etiología de la Enfermedad de Alzheimer. Este es un tema complejo, pues varios procesos, enzimáticos y no-enzimáticos, están implicados en la formación de oxígeno reactivo y otras moléculas tóxicas. En este artículo discutimos el progreso en el entendimiento de estos procesos[EN]: Oxidative stress is the earliest feature of Alzheimer disease and an attractive therapeutic target. One of the major challenges today is to establish the source of the reactive oxygen and to determine the role of oxidative stress in the etiology of Alzheimer disease. This is a complex issue since a variety of enzymatic and non-enzymatic processes are involved in the formation of reactive oxygen and other toxic molecules. In this review, we discuss progress in the understanding of these processes.Peer reviewe

Is oxidative damage the fundamental pathogenic mechanism of Alzheimer’s and other neurodegenerative diseases?

In less than a decade, beginning with the demonstration by Floyd, Stadtman, Markesbery et al. [1] of increased reactive carbonyls in the brains of patients with Alzheimer’s disease (AD), oxidative damage has been established as a feature of the disease. Here, we review the types of oxidative damage seen in AD, sites involved, possible origin, relationship to lesions, and compensatory changes, and we also consider other neurodegenerative diseases where oxidative stress has been implicated. Although much data remain to be collected, the broad spectrum of changes found in AD are only seen, albeit to a lesser extent, in normal aging with other neurodegenerative diseases showing distinct spectrums of change.Work in the authors’ laboratories is supported by funding from the National Institutes of Health (NS38648, AG19356, AG14249) and the Alzheimer’s Association (IIRG-98-136, ZEN-99-1789, IIRG-00-2163-Stephanie B. Overstreet Scholars, IIRG-98-140, TLL-99-1872).Peer reviewe

Nitric Oxide-Dependent Oxidative Stress Induced Mitochondrial DNA Overproliferation and Deletion in the Context of Cancer and Alzheimer Disease

Oxidative stress initiates mitochondrial DNA overproliferation and/or deletion of the organ and/or tissues, especially the mitochondrial energy demands, have been implicated in the pathogenesis of several diseases, including Alzheimer disease (AD), tumor growth, and metastasis. The present study has determined if an intimate, i.e. causal, relationship between oxidative stress and mitochondrial damage and/or vascular lesions occurs before the development of human AD, in animal models that mimic human neurodegenerative diseases and human colorectal carcinoid cancer or primary malignant brain cancer. In situ hybridization and ultrastructural analysis of the mitochondria (mitochondria with electron dense matrix, mitochondrial-derived lysosomes) showed that mitochondria with the abnormal structures and lipofuscin appear to be features of hippocampal damaged neurons in human AD, aged Tg (+) mice, 2 and 3 vessel occlusion model of the brain hypoperfusion, and malignant primary and metastatic cancer. The abnormal mitochondria appeared to be a permanent feature in all cellular compartments; in situ hybridization analysis with mouse and human mtDNA probes found a large amount of deleted mtDNA in human AD and in all models that mimic human AD (mice, rats etc.) hippocampus and cancer tissues compared to aged controls. The majority of these mtDNA deletions were found in mitochondrial-derived lysosomes in regions closely associated with lipofuscin and/or tumor growth regions. In situ hybridization with a chimeric cDNA probe for the 5kb common deletion indicated that the 5kb mtDNA is increased at least 3 and 4 fold respectively in AD and malignant tumor cases as compared to controls. Only hippocampal and cortical vulnerable neurons as well as malignant cancer tissues showed immunopositive staining for RNA oxidation markers visualized by using 8-OHG-staining, NOSs, and all oxidative stress markers. The mitochondrial DNA overproliferation and deletion detected by using cytological techniques suggests that successful dysregulation of the cell cycle is also the hallmark of neoplasm; early mitochondrial dependent cell-cycle pathophysiology in AD may recruit oncogenic signal transduction mechanisms and hence, can be viewed as an abortive neoplastic transformation. The common features on the mitochondrial abnormality were seen on the brain during tumorigenesis and AD indicating that mitochondrial DNA overproliferation and/or deletion are the key initiating factors for development, maturation, and progression of neurodegeneration as well as tumor growth and/or metastases. Materials presented in this work indicate that the Nitric oxide- (NO-) dependent oxidative stress results in mitochondrial ultrastructural alterations and DNA damage in cases of Alzheimer disease (AD). However, little is known about these pathways in human cancers, especially during the development as well as the progression of primary brain tumors and metastatic colorectal cancer. One of the key features of tumors is the deficiency in tissue energy that accompanies mitochondrial lesions and formation of the hypoxic smaller sized mitochondria with ultrastructural abnormalities. We theorize that mitochondrial involvement may play a significant role in the etiopathogenesis of cancer. Moreover, our study also demonstrates a potential link between AD and cancer, and anticancer drugs are being explored for the inhibition of AD-like pathology in transgenic mice. Severity of the cancer growth, metastasis, and brain pathology in AD (in animal models that mimic human AD) correlate with the degree of mitochondrial ultrastructural abnormalities. Recent advances in the cell-cycle reentry of the terminally differentiated neuronal cells indicate that NO-dependent mitochondrial abnormal activities and mitotic cell division are not the only important pathogenic factors in pathogenesis of cancer and AD, but open a new window for the development of novel treatment strategies for these devastating diseases

Implication of Integrative Treatment Strategies for Real-Life Geriatric Patients with Multiple, Chronic Illnesses: A 60-Month Follow-Up of a Naturalistic Study

Neurodegeneration [Stroke and Alzheimer disease (AD)] is fastly becoming one of the leading causes of age-associated disability, dementia, and death. In addition, the Centers for Disease Control and Prevention (CDC) and the National Center for Health Statistics recently reported that AD has surpassed diabetes as a leading cause of death and is now considered the sixth-leading cause of death in the United States. Unfortunately, currently no effective treatments are available against this devastating disease. In the past we have shown the preservation and improvement of cognitive tasks in depressed and demented patients after 24 and 36 months of combined pharmacological and non- pharmacological treatment. Here we present the results of our ongoing, naturalistic study, in the same outpatient setting, at the 60 month follow up. The study group consisted of 156 medically ill, physically-disabled patients with mild to moderate dementia and depression. Patients were treated with antidepressants, cholinesterase inhibitors, and NMDA antagonists, along with their regular medication regimen. Non-pharmacological intervention was centered on a home-based program of physical and cognitive exercises as well as with vitamins and supplements (multivitamins, vitamin E, L-methylfolate, alpha-lipoic acid, acetyl-l-carnitine, omega-3, and coenzyme Q-10) and diet modification. Cognitive assessments were performed yearly. After 60 months of treatment, performance of all tasks remained at or above baseline. The MMSE, Cognistat–Attention, Cognistat–Judgment, and RFFT - Total Unique Designs demonstrated significant improvement. Our results, for the first time, demonstrate arrest in cognitive decline in demented/depressed patients with multiple medical co-morbidities for 60 months. Future investigations addressing the application of a combined, integrative treatment models in clinical practices are warranted