Protein Homeostasis, Aging and Alzheimer’s Disease

Alzheimer's disease (AD) is one key medical challenge of the aging society and despite a great amount of effort and a huge collection of acquired data on molecular mechanisms that are associated with the onset and progression of this devastating disorder, no causal therapy is in sight. The two main hypotheses of AD, the amyloid cascade hypothesis and the Tau hypothesis, are still in the focus of AD research. With aging as the accepted main risk factor of the most important non familial and late onset sporadic forms of AD, it is now mandatory to discuss more intensively aspects of cellular aging and aging biochemistry and its impact on neurodegeneration. Since aging is accompanied by changes in cellular protein homeostasis and an increasing demand for protein degradation, aspects of protein folding, misfolding, refolding and, importantly, protein degradation need to be linked to AD pathogenesis. This is the purpose of this short review.     

Ca2+ dysfunction in neurodegenerative disorders: Alzheimer's disease

More than one century ago "a peculiar disorder of the cerebral cortex" was noticed in a middle-aged patient who had been affected by dementia in the last years of his life. The postmortem hallmarks of his brain were protein plaques, neurofibrillary tangles, and atherosclerotic changes: the neuropathologist who found these alterations and gave his name to the disease that underlied them was Alois Alzheimer (Alzheimer et al., Clin Anat 1995;8:429-431). Following its discovery, the disease has been studied with a vigor that went parallel to the increase of its social importance. The amount of information amassed in the literature is impressive, but knowledge on the mechanism underlying its onset and its progression is still very limited. Numerous hypotheses on the molecular pathogenesis of the Alzheimer's disease (AD) have been proposed and two have gradually gained wide consensus: (i) the amyloid cascade hypothesis, first proposed on the basis of the toxicity evoked by the deposition of amyloid β (Aβ) aggregates; (ii) the Ca(2+) hypothesis, which focuses on the correlation between the dysfunction of Ca(2+) homeostasis and the neurodegeneration process. This succinct review will discuss the essential aspects of the role of Ca(2+) homeostasis dysregulation in the onset and development of AD.     

The Senescence Hypothesis of Disease Progression in Alzheimer Disease: an Integrated Matrix of Disease Pathways for FAD and SAD

Alzheimer disease (AD) is a progressive, neurodegenerative disease characterised in life by cognitive decline and behavioural symptoms and post-mortem by the neuropathological hallmarks including the microtubule-associated protein tau-reactive tangles and neuritic plaques and amyloid-beta-protein-reactive senile plaques. Greater than 95 % of AD cases are sporadic (SAD) with a late onset and <5 % of AD cases are familial (FAD) with an early onset. FAD is associated with various genetic mutations in the amyloid precursor protein (APP) and the presenilins (PS)1 and PS2. As yet, no disease pathway has been fully accepted and there are no treatments that prevent, stop or reverse the cognitive decline associated with AD. Here, we review and integrate available environmental and genetic evidence associated with all forms of AD. We present the senescence hypothesis of AD progression, suggesting that factors associated with AD can be seen as partial stressors within the matrix of signalling pathways that underlie cell survival and function. Senescence pathways are triggered when stressors exceed the cells ability to compensate for them. The APP proteolytic system has many interactions with pathways involved in programmed senescence and APP proteolysis can both respond to and be driven by senescence-associated signalling. Disease pathways associated with sporadic disease may be different to those involving familial genetic mutations. The interpretation we provide strongly points to senescence as an additional underlying causal process in dementia progression in both SAD and FAD via multiple disease pathways.     

Alzheimer's disease: cholesterol, membrane rafts, isoprenoids and statins

Alzheimer''s disease (AD) is a heterogeneous neurodegenerative disorder and the most prevalent form of dementia worldwide. AD is characterized pathologically by amyloid-β plaques, neurofibrillary tangles and neuronal loss, and clinically by a progressive loss of cognitive abilities. At present, the fundamental molecular mechanisms underlying the disease are unclear and no treatment for AD is known. Epidemiological evidence continues to mount linking vascular diseases, such as hypertension and diabetes, and hypercholesterolaemia with an increased risk for developing AD. A growing amount of evidence suggests a mechanistic link between cholesterol metabolism in the brain and the formation of amyloid plaques in AD development. Cholesterol and statins clearly modulate β-amyloid precursor protein (βAPP) processing in cell culture and animal models. Statins not only reduce endogenous cholesterol synthesis but also exert other various pleiotrophic effects, such as the reduction in protein isoprenylation. Through these effects statins modulate a variety of cellular functions involving both cholesterol (and membrane rafts) and isoprenylation. Although clearly other factors, such as vascular inflammation, oxidative stress and genetic factors, are intimately linked with the progression of AD, this review focuses on the present research findings describing the effect of cholesterol, membrane rafts and isoprenylation in regulating βAPP processing and in particular γ-secretase complex assembly and function and AD progression, along with consideration for the potential role statins may play in modulating these events.     

Down syndrome,Alzheimer disease,and cerebral amyloid angiopathy: The complex triangle of brain amyloidosis

Down syndrome (DS) is the main genetic cause of intellectual disability worldwide. The overexpression of the Amyloid Precursor Protein, present in chromosome 21, leads to β‐amyloid deposition that results in Alzheimer disease (AD) and, in most cases, also to cerebral amyloid angiopathy (CAA) neuropathology. People with DS invariably develop the neuropathological hallmarks of AD at the age of 40, and they are at an ultra high risk for suffering AD‐related cognitive impairment thereafter. In the general population, cerebrovascular disease is a significant contributor to AD‐related cognitive impairment, while in DS remains understudied. This review describes the current knowledge on cerebrovascular disease in DS and reviews the potential biomarkers that could be useful in the future studies, focusing on CAA. We also discuss available evidence on sporadic AD or other genetically determined forms of AD. We highlight the urgent need of large biomarker‐characterized cohorts, including neuropathological correlations, to study the exact contribution of CAA and related vascular factors that play a role in cognition and occur with aging, their characterization and interrelationships. DS represents a unique context in which to perform these studies as this population is relatively protected from some conventional vascular risk factors and they develop significant CAA, DS represents a particular atheroma‐free model to study AD‐related vascular pathologies. Only deepening on these underlying mechanisms, new preventive and therapeutic strategies could be designed to improve the quality of life of this population and their caregivers and lead to new avenues of treatment also in the general AD population.     

Interactions between the amyloid and cholinergic mechanisms in Alzheimer's disease

Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by memory and cognitive loss, the formation of senile plaques containing amyloid-beta (Abeta) peptide, degeneration of the cholinergic neurons and the development of neurofibrillary tangles. The build-up of Abeta is considered to be a central feature in the pathogenesis of AD. However, other critical molecular and neurochemical alterations too occur, such as a cholinergic dysfunction. As concerns the pathomechanism of the disease, both the amyloid cascade hypothesis and the cholinergic hypothesis of AD are widely accepted. This review surveys recent in vitro and in vivo experimental evidence relating to these two hypotheses. Bidirectional pathways linking them as regards the cholinergic neurotoxicity of Abeta and the regulatory mechanisms of cholinergic receptor activation or enzyme inhibition in the processing of the amyloid precursor protein are also discussed. Further work is warranted to elucidate the exact effects in the interactions between the cholinergic and amyloid hypotheses of the candidate drugs used in AD therapy.     

The missing link in the amyloid cascade of Alzheimer’s disease – Metal ions

Progressive deposition of amyloid beta (Aβ) peptides into amyloid plaques is the pathological hallmark of Alzheimer’s disease (AD). The amyloid cascade hypothesis pins this deposition as the primary cause of the disease, but the mechanisms that causes this deposition remain elusive. An increasing amount of evidence shows that biometals Zn(II) and Cu(II) can interact with Aβ, thus influencing the fibrillization and toxicity. This review focuses on the role of Zn(II) and Cu(II) in AD, and revisits the amyloid cascade hypothesis demonstrating the possible roles of Zn(II) and Cu(II) in the disease pathogenesis.     

Calcium dysregulation in Alzheimer's disease

Alzheimer disease (AD) is the most common form of adult dementia. Its pathological hallmarks are synaptic degeneration, deposition of amyloid plaques and neurofibrillary tangles, leading to neuronal loss. A few hypotheses have been proposed to explain AD pathogenesis. The beta-amyloid (Abeta) and hyperphosphorylated tau hypotheses suggest that these proteins are the main players in AD development. Another hypothesis proposes that the dysregulation of calcium homeostasis may be a key factor in accelerating other pathological changes. Although Abeta and tau have been extensively studied, recently published data provide a growing body of evidence supporting the critical role of calcium signalling in AD. For example, presenilins, which are mutated in familial cases of AD, were demonstrated to form low conductance calcium channels in the ER and elevated cytosolic calcium concentration increases amyloid generation. Moreover, memantine, an antagonist of the NMDA-calcium channel receptor, has been found to have a beneficial effect for AD patients offering novel possibilities for a calcium signalling targeted therapy of AD. This review underscores the growing importance of calcium ions in AD development and focuses on the relevant aspects of calcium homeostasis.     

Abeta,oxidative stress in Alzheimer disease: Evidence based on proteomics studies

The initiation and progression of Alzheimer disease (AD) is a complex process not yet fully understood. While many hypotheses have been provided as to the cause of the disease, the exact mechanisms remain elusive and difficult to verify. Proteomic applications in disease models of AD have provided valuable insights into the molecular basis of this disorder, demonstrating that on a protein level, disease progression impacts numerous cellular processes such as energy production, cellular structure, signal transduction, synaptic function, mitochondrial function, cell cycle progression, and proteasome function. Each of these cellular functions contributes to the overall health of the cell, and the dysregulation of one or more could contribute to the pathology and clinical presentation in AD. In this review, foci reside primarily on the amyloid β-peptide (Aβ) induced oxidative stress hypothesis and the proteomic studies that have been conducted by our laboratory and others that contribute to the overall understanding of this devastating neurodegenerative disease. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases.     

综述:靶向淀粉样蛋白的阿尔茨海默病药物研究进展

淀粉样蛋白级联假说是阐释阿尔茨海默病(Alzheimer's disease,AD)发病机制的主要学说之一,即脑内过量的β-淀粉样蛋白(β-amyloid,Aβ)是促发AD的核心因素．因此,靶向Aβ形成、聚集和清除等关键环节的药物开发是目前药物研究的热点．但近年来AD新药临床试验屡屡失败,至今尚未得到一种切实有效的治疗药物．淀粉样蛋白级联假说的局限性和痴呆期患者疾病进程的难以逆转,可能是临床试验反复失败的两个主要原因．借助AD早期诊断技术的发展,将药物干预的时间窗口前移,重视痴呆前期病理机制与治疗的研究,可能是研制延缓AD发生和发展有效药物的新途径．     

Alzheimer's disease untangled.

The last year has seen major advances in the study of Alzheimer's disease (AD). Four mutations involving amino acid substitutions in exons 16 and 17 of the amyloid precursor protein (APP) gene, have been identified which co-segregate with the disease in some families multiply affected by early onset Alzheimer's disease. These mutations are strongly suggestive of a causative role for the amyloid precursor protein in Alzheimer's disease. Despite their rarity, these mutations are important because they represent the first known cause of Alzheimer's disease. Processing of APP must be central to the pathogenesis of the disease although the precise effects of these amino acid substitutions are not understood. Work is now being undertaken to characterise the processing pathways of APP and to identify other causes of AD. The development of models of AD using the APP mutations offers the possibility of identifying drug targets and developing more effective treatments than are presently available.     

Antioxidant clinical trials in mild cognitive impairment and Alzheimer's disease

Alzheimer's disease (AD) is a highly disabling progressive neurodegenerative disorder characterized by a steadily growing number of patients, by the absence of a cure for the disease and by great difficulties in diagnosing in the preclinical phase. Progresses in defining the complex etiopathogenesis of AD consider oxidative stress a core aspect as far as both AD onset and progression are concerned. However, clinical trials of antioxidants in AD have brought conflicting conclusions. In this review, we report the main results of clinical trials with antioxidants in mild cognitive impairment (MCI) and AD. Although available data do not warrant the doubtless use of antioxidants in AD, they are characterized by extremely poor comparability and the absence of a substantial clinical benefit of antioxidants in AD is not disproved to date. Furthermore, the role of vascular damage that contributes to oxidative stress in AD should be addressed in testing antioxidant treatments. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.     

'Alzheimer-like' pathology in a murine model of arterial hypertension

Genetic AD (Alzheimer's disease) accounts for only few AD cases and is almost exclusively associated with increased amyloid production in the brain. Instead, most patients are affected with the sporadic form of AD and typically have altered clearance mechanisms. The identification of factors that influence the onset and progression of sporadic AD is a key step towards understanding its mechanism(s) and developing successful therapies. An increasing number of epidemiological studies describe a strong association between AD and cardiovascular risk factors, particularly hypertension, that exerts detrimental effects on the cerebral circulation, favouring chronic brain hypoperfusion. However, a clear demonstration of a pathophysiological link between cardiovascular risk factors and AD aetiology is still missing. To increase our knowledge of the mechanisms involved in the brain's response to hypertension and their possible role in promoting amyloid deposition in the brain, we have performed and investigated in depth different murine models of hypertension, induced either pharmacologically or mechanically, leading in the long term to plaque formation in the brain parenchyma and around blood vessels. In the present paper, we review the major findings in this particular experimental setting that allow us to study the pathogenetic mechanisms of sporadic AD triggered by vascular risk factors.     

Neuroimaging Results Impose New Views on Alzheimer’s Disease—the Role of Amyloid Revised

Huge progress has been made in unraveling the mysteries of Alzheimer’s disease (AD), but we still do not understand the basic mechanisms that set off the cascade of pathological events. In May 2011, the National Institute on Aging–Alzheimer’s Association published new diagnostic guidelines, expected to have huge impact on AD research and clinical practice. However, the new guidelines are already criticized for being biased in favor of a specific theory of the pathophysiological origins of AD—the amyloid cascade hypothesis. Shortly before publication of the guidelines, a hypothetical model of the dynamic biomarkers of the Alzheimer’s pathological cascade was published, taking as starting point that biomarkers reflecting brain levels of amyloid become deviant long before brain atrophy, cognitive dysfunction, or clinical symptoms are manifest. This model has already attracted substantial interest and arguably represents a dominating view within human research on AD. Here we critically review the evidence for the view of amyloid as an initiating event in the pathological cascade and discuss how central assumptions of this hypothesis affect how results from contemporary human AD research are understood. Interpretations of new results are greatly impacted by researchers’ view on the role of amyloid, and identical observations are sometimes taken to support radically opposing views on the amyloid hypothesis. We argue that the canonical view of the role of amyloid as the main causal factor in AD may not be correct and that evidence from recent neuroimaging studies indicates that amyloid is neither necessary nor sufficient, for the manifestation of AD-like brain atrophy.     

Aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer's disease: implications for early intervention and therapeutics

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disease affecting thousands of people in the world and effective treatment is still not available. Over two decades of intense research using AD postmortem brains, transgenic mouse and cell models of amyloid precursor protein and tau revealed that amyloid beta (Aβ) and hyperphosphorylated tau are synergistically involved in triggering disease progression. Accumulating evidence also revealed that aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction initiate and contributes to the development and progression of the disease. The purpose of this article is to summarize the latest progress in aging and AD, with a special emphasis on the mitochondria, oxidative DNA damage including methods of its measurement. It also discusses the therapeutic approaches against oxidative DNA damage and treatment strategies in AD.     

Mitochondria as a primary target for vascular hypoperfusion and oxidative stress in Alzheimer's disease

It has been widely accepted that vascular hypoperfusion induces oxidative stress and the outcome of this misbalance is brain energy failure. This abnormality leads to neuronal death which manifests as cognitive impairment and the development of brain pathology as in Alzheimer's disease (AD). It has been demonstrated that the AD brain is characterized by impairments in energy metabolism. We theorize that hypoperfusion induced mitochondrial failure plays a key role in the generation of reactive oxygen species, resulting in oxidative damage to brain cellular compartments, especially in the vascular endothelium and in selective population of neurons with high metabolic activity in the AD brain. All of these abnormalities have been found to occur before classic AD pathology inducing neuronal degeneration and amyloid deposition during the progression of AD. Therefore, expanding investigations into both the mechanisms behind amyloid beta (Abeta) deposition and the possible accelerating effects of environmental factors such as chronic hypoxia/reperfusion may open a new avenue for effective treatments of AD. Future studies examining the importance of mitochondrial pathobiology in brain cellular compartments provide insight not only into the better understanding of the neurodegenerative and/or cerebrovascular disease but also provide targets for treating these conditions.     

Amyloid PET: Its diagnostic potential compared to FDG

Amyloid PET using high-affinity ligands for fibrillary amyloid is providing high specificity and sensitivity for detection of Alzheimer's disease (AD) even before onset of dementia. Most current published data have been acquired using 11C-Pittsburgh Compound B (PIB). However, due to the extremely short half-life of 11C, PIB is available only in some research laboratories. This limitation will be overcome by 18F-labeled ligands which are currently undergoing formal clinical trials as amyloid imaging agents and are expected to become commercially available for clinical use in the near future. Compared to FDG, which demonstrates regional metabolic deficits in AD and late-stage mild cognitive impairment (MCI), amyloid imaging is expected to provide higher sensitivity for early detection of AD. By detecting amyloid, it is providing information that is complementary to clinical symptoms, while FDG-PET is more closely related to dementia severity and cognitive symptoms. Current data suggest that a negative amyloid PET scan is likely to rule out AD with more than 90% certainty, while a positive scan in a dementia patient or a patient with amnestic MCI indicates a very high likelihood of AD. There is still uncertainty about the clinical significance of positive amyloid scans in elderly normal controls (10 to 40% depending on age and selection criteria).