Autophagy Modulation for Alzheimer’s Disease Therapy

Autophagy is an essential and conserved lysosomal degradation pathway that controls the quality of cytoplasm by eliminating the intracellular aggregated proteins and damaged organelles. Autophagy works in mammalian target of rapamycin (mTOR)-dependent pathway or mTOR-independent pathway to keep the neuronal homeostasis. Mounting evidence has implicated the importance of defective autophagy in the pathogenesis of aging and neurodegenerative diseases, especially in Alzheimer’s disease (AD). It has also demonstrated a neuroprotective role of autophagy in mediating the degradation of amyloid beta and tau which are major factors of AD. Amounts of molecules function in either mTOR-dependent pathway or mTOR-independent pathway to induce autophagy, which maybe a potential treatment for AD. In this review, we summarize the latest studies concerning the role of autophagy in AD and explore autophagy modulation as a potential therapeutic strategy for AD. However, to date, little of the researches on autophagy have been performed to investigate the modulation in AD; more investigations need to be confirmed in the future.     

Synapses and Alzheimer’s Disease

Alzheimer’s disease (AD) is a major cause of dementia in the elderly. Pathologically, AD is characterized by the accumulation of insoluble aggregates of Aβ-peptides that are proteolytic cleavage products of the amyloid-β precursor protein (“plaques”) and by insoluble filaments composed of hyperphosphorylated tau protein (“tangles”). Familial forms of AD often display increased production of Aβ peptides and/or altered activity of presenilins, the catalytic subunits of γ-secretase that produce Aβ peptides. Although the pathogenesis of AD remains unclear, recent studies have highlighted two major themes that are likely important. First, oligomeric Aβ species have strong detrimental effects on synapse function and structure, particularly on the postsynaptic side. Second, decreased presenilin function impairs synaptic transmission and promotes neurodegeneration. The mechanisms underlying these processes are beginning to be elucidated, and, although their relevance to AD remains debated, understanding these processes will likely allow new therapeutic avenues to AD.Alzheimer’s disease (AD) is a common neurodegenerative disease of the elderly, first described by the physician-pathologist Alois Alzheimer in 1907 (Maurer and Maurer 2003). Clinically, AD is characterized by progressive impairment of memory (particularly short-term memory in early stages) and other cognitive disabilities, personality changes, and ultimately, complete dependence on others. The most prevalent cause of dementia worldwide, AD afflicts >5 million people in the United States and >25 million globally (Alzheimer’s Association, http://www.alz.org). Age is the most important risk factor, with the prevalence of AD rising exponentially after 65 (Blennow et al. 2006). However, many cases of so-called AD above 80 yr of age may result from a combination of pathological dementia processes (Fotuhi et al. 2009). The apolipoprotein E (ApoE) gene is the most important genetic susceptibility factor for AD, with the relatively common ApoE4 allele (prevalence ∼16%) increasing the risk for AD threefold to fourfold in heterozygous dose (Kim et al. 2009).The histopathological hallmarks of AD are amyloid plaques (extracellular deposits consisting largely of aggregated amyloid beta [Aβ] peptide that are typically surrounded by neurons with dystrophic neurites) and neurofibrillary tangles (NFTs, intracellular filamentous aggregates of hyperphosphorylated tau, a microtubule-binding protein) (Blennow et al. 2006). The development of amyloid plaques typically precedes clinically significant symptoms by at least 10–15 yr. Amyloid plaques are found in a minority of nondemented elderly patients, who may represent a “presymptomatic” AD population. As AD progresses, cognitive function worsens, synapse loss and neuronal cell death become prominent, and there is substantial reduction in brain volume, especially in the entorhinal cortex and hippocampus. The best correlation between dementia and histopathological changes is observed with neurofibrillary tangles, whereas the relationship between the density of amyloid plaques and loss of cognition is weaker (Braak and Braak 1990; Nagy et al. 1995). In addition to amyloid plaques and neurofibrillary tangles, many AD cases exhibit widespread Lewy body pathology. (Lewy bodies are intracellular inclusion bodies that contain aggregates of α-synuclein and other proteins.) Particularly in very old patients, considerable overlap between AD, frontotemporal dementia, Lewy body dementia, and vascular disease is observed, and pure AD may be rare (Fotuhi et al. 2009).     

Neuronal Autophagy: Self-eating or Self-cannibalism in Alzheimer’s Disease

Autophagy is a major intracellular degeneration pathway involved in the elimination and recycling of damaged organelles and long-lived proteins by lysosomes. Many of the pathological factors, which trigger neurodegenerative diseases, can perturb the autophagy activity, which is associated with misfolded protein aggregates accumulation in these disorders. Alzheimer’s disease, the first neurodegenerative disorder between dementias, is characterized by two aggregating proteins, β-amyloid peptide (plaques) and τ-protein (tangles). In Alzheimer’s disease autophagosomes dynamically form along neurites within neuronal cells and in synapses but effective clearance of these structures needs retrograde transportation towards the neuronal soma where there is a major concentration of lysosomes. Maturation of autophago-lysosomes and their retrograde trafficking are perturbed in Alzheimer’s disease, which causes a massive concentration of autophagy elements along degenerating neurites. Transportation system is disturbed along defected microtubules in Alzheimer’s disease brains. τ-protein has been found to control the stability of microtubules, however, phosphorylation of τ-protein or an increase in the total level of τ-protein can cause dysfunction of neuronal cells microtubules. Current evidence has shown that autophagy is developing in Alzheimer’s disease brains because of ineffective degradation of autophagosomes, which hold amyloid precursor protein-rich organelles and secretases important for β-amyloid peptides generation from amyloid precursor. The combination of raised autophagy induction and abnormal clearance of β-amyloid peptide-generating autophagic vacuoles creates circumstances helpful for β-amyloid peptide aggregation and accumulation in Alzheimer’s disease. However, the key role of autophagy in Alzheimer’s disease development is still under consideration today. One point of view suggests that abnormal autophagy induction causes a concentration of autophagic vacuoles rich in amyloid precursor protein, β-amyloid peptide and the elements crucial for its formation, whereas other hypothesis points to marred autophagic clearance or even decrease in autophagic effectiveness playing a role in maturation of Alzheimer’s disease. In this review we present the recent evidence linking autophagy to Alzheimer’s disease and the role of autophagic regulation in the development of full-blown Alzheimer’s disease.     

Calcium Signalling and Alzheimer’s Disease

New insights into how Ca²⁺ regulates learning and memory have begun to provide clues as to how the amyloid-dependent remodelling of neuronal Ca²⁺ signalling pathways can disrupt the mechanisms of learning and memory in Alzheimer’s disease (AD). The calcium hypothesis of AD proposes that activation of the amyloidogenic pathway remodels the neuronal Ca²⁺ signalling pathways responsible for cognition by enhancing the entry of Ca²⁺ and/or the release of internal Ca²⁺ by ryanodine receptors or InsP₃ receptors. The specific proposal is that Ca²⁺ signalling remodelling results in a persistent elevation in the level of Ca²⁺ that constantly erases newly acquired memories by enhancing the mechanism of long-term depression (LTD). Neurons can still form memories through the process of LTP, but this stored information is rapidly removed by the persistent activation of LTD. Further dysregulation in Ca²⁺ signalling will then go on to induce the neurodegeneration that characterizes the later stages of dementia.     

Expression of Novel Alzheimer’s Disease Risk Genes in Control and Alzheimer’s Disease Brains

Late onset Alzheimer’s disease (LOAD) etiology is influenced by complex interactions between genetic and environmental risk factors. Large-scale genome wide association studies (GWAS) for LOAD have identified 10 novel risk genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A6E, and PICALM. We sought to measure the influence of GWAS single nucleotide polymorphisms (SNPs) and gene expression levels on clinical and pathological measures of AD in brain tissue from the parietal lobe of AD cases and age-matched, cognitively normal controls. We found that ABCA7, CD33, and CR1 expression levels were associated with clinical dementia rating (CDR), with higher expression being associated with more advanced cognitive decline. BIN1 expression levels were associated with disease progression, where higher expression was associated with a delayed age at onset. CD33, CLU, and CR1 expression levels were associated with disease status, where elevated expression levels were associated with AD. Additionally, MS4A6A expression levels were associated with Braak tangle and Braak plaque scores, with elevated expression levels being associated with more advanced brain pathology. We failed to detect an association between GWAS SNPs and gene expression levels in our brain series. The minor allele of rs3764650 in ABCA7 is associated with age at onset and disease duration, and the minor allele of rs670139 in MS4A6E was associated with Braak tangle and Braak plaque score. These findings suggest that expression of some GWAS genes, namely ABCA7, BIN1, CD33, CLU, CR1 and the MS4A family, are altered in AD brains.     

Brain Under Stress and Alzheimer’s Disease

Modern society is characterized by the ubiquity of stressors that affect every individual to different extents. Furthermore, experimental, clinical, and epidemiological data have shown that chronic activation of the stress response may participate in the development of various somatic as well as neuropsychiatric diseases. Surprisingly, the role that stress plays in the etiopathogenesis of Alzheimer’s disease (AD) has not yet been studied in detail and is therefore not well understood. However, accumulated data have shown that neuroendocrine and behavioral changes accompanying the stress response affect neuronal homeostasis and compromise several key neuronal processes. Mediators of the neuroendocrine stress response, if elevated repeatedly or chronically, exert direct detrimental effects on the brain by impairing neuronal metabolism, plasticity, and survival. Stress-induced hormonal and behavioral reactions may also participate in the development of hypertension, atherosclerosis, insulin resistance, and other peripheral disturbances that may indirectly induce neuropathological processes participating in the development and progression of AD. Importantly, stress-induced detrimental effects as etiological factors of AD are attractive because they can be reduced by several approaches including behavioral and pharmacological interventions. These interventions may therefore represent an important strategy for prevention or attenuation of the progression of AD.     

The Endocannabinoid System and Alzheimer’s Disease

The importance of the role of the endocannabinoid system (ECS) in neurodegenerative diseases has grown during the past few years. Mostly because of the high density and wide distribution of cannabinoid receptors of the CB₁ type in the central nervous system (CNS), much research focused on the function(s) that these receptors might play in pathophysiological conditions. Our current understanding, however, points to much diverse roles for this system. In particular, other elements of the ECS, such as the fatty acid amide hydrolase (FAAH) or the CB₂ cannabinoid receptor are now considered as promising pharmacological targets for some diseases and new cannabinoids have been incorporated as therapeutic tools. Although still preliminary, recent reports suggest that the modulation of the ECS may constitute a novel approach for the treatment of Alzheimer’s disease (AD). Data obtained in vitro, as well as in animal models for this disease and in human samples seem to corroborate the notion that the activation of the ECS, through the use of agonists or by enhancing the endogenous cannabinoid tone, may induce beneficial effects on the evolution of this disease.     

Natural Antioxidants Protect Neurons in Alzheimer’s Disease and Parkinson’s Disease

“Modern” medicine and pharmacology require an effective medical drug with a single compound for a specific disease. This seams very scientific but usually has unavoidable side effects. For example, the chemical therapy to cancer can totally damage the immunological ability of the patient leading to death early than non-treatment. On the other hand, natural antioxidant drugs not only can cure the disease but also can enhance the immunological ability of the patient leading to healthier though they usually have several compounds or a mixture. For the degenerative disease such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), natural antioxidant drugs are suitable drugs, because the pathogenesis of these diseases is complex with many targets and pathways. These effects are more evidence when the clinic trial is for long term treatment. The author reviews the studies on the protecting effects of natural antioxidants on neurons in neurodegenerative diseases, especially summarized the results about protective effect of green tea polyphenols on neurons against apoptosis of cellular and animal PD models, and of genestine and nicotine on neurons against Aβ—induced apoptosis of hippocampal neuronal and transgenic mouse AD models. Special issue in honor of Dr. Akitane Mori.     

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.     

Periodontitis and Cognitive Decline in Alzheimer’s Disease

Periodontitis is common in the elderly and may become more common in Alzheimer’s disease because of a reduced ability to take care of oral hygiene as the disease progresses. Elevated antibodies to periodontal bacteria are associated with an increased systemic pro-inflammatory state. Elsewhere raised serum pro-inflammatory cytokines have been associated with an increased rate of cognitive decline in Alzheimer’s disease. We hypothesized that periodontitis would be associated with increased dementia severity and a more rapid cognitive decline in Alzheimer’s disease. We aimed to determine if periodontitis in Alzheimer’s disease is associated with both increased dementia severity and cognitive decline, and an increased systemic pro inflammatory state. In a six month observational cohort study 60 community dwelling participants with mild to moderate Alzheimer’s Disease were cognitively assessed and a blood sample taken for systemic inflammatory markers. Dental health was assessed by a dental hygienist, blind to cognitive outcomes. All assessments were repeated at six months. The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a six fold increase in the rate of cognitive decline as assessed by the ADAS-cog over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six month follow up period. Our data showed that periodontitis is associated with an increase in cognitive decline in Alzheimer’s Disease, independent to baseline cognitive state, which may be mediated through effects on systemic inflammation.     

Sporadic Alzheimer’s Disease Begins as Episodes of Brain Ischemia and Ischemically Dysregulated Alzheimer’s Disease Genes

The study of sporadic Alzheimer’s disease etiology, now more than ever, needs an infusion of new concepts. Despite ongoing interest in Alzheimer’s disease, the basis of this entity is not yet clear. At present, the best-established and accepted “culprit” in Alzheimer’s disease pathology by most scientists is the amyloid, as the main molecular factor responsible for neurodegeneration in this disease. Abnormal upregulation of amyloid production or a disturbed clearance mechanism may lead to pathological accumulation of amyloid in brain according to the “amyloid hypothesis.” We will critically review these observations and highlight inconsistencies between the predictions of the “amyloid hypothesis” and the published data. There is still controversy over the role of amyloid in the pathological process. A question arises whether amyloid is responsible for the neurodegeneration or if it accumulates because of the neurodegeneration. Recent evidence suggests that the pathophysiology and neuropathology of Alzheimer’s disease comprises more than amyloid accumulation, tau protein pathology and finally brain atrophy with dementia. Nowadays, a handful of researchers share a newly emerged view that the ischemic episodes of brain best describe the pathogenic cascade, which eventually leads to neuronal loss, especially in hippocampus, with amyloid accumulation, tau protein pathology and irreversible dementia of Alzheimer type. The most persuasive evidences come from investigations of ischemically damaged brains of patients and from experimental ischemic brain studies that mimic Alzheimer-type dementia. This review attempts to depict what we know and do not know about the triggering factor of the Alzheimer’s disease, focusing on the possibility that the initial pathological trigger involves ischemic episodes and ischemia-induced gene dysregulation. The resulting brain ischemia dysregulates additionally expression of amyloid precursor protein and amyloid-processing enzyme genes that, in addition, ultimately compromise brain functions, leading over time to the complex alterations that characterize advanced sporadic Alzheimer’s disease. The identification of the genes involved in Alzheimer’s disease induced by ischemia will enable to further define the events leading to sporadic Alzheimer’s disease-related abnormalities. Additionally, knowledge gained from the above investigations should facilitate the elaboration of the effective treatment and/or prevention of Alzheimer’s disease.     

Lyme Disease Associated with Alzheimer’s Disease

This case report discusses a patient with co-occurring neuroborreliosis and Alzheimer’s disease (AD). Although no claim is made for causality nor is there objective evidence that spirochetes are involved in AD, co-infection may exacerbate the symptoms of either neuroborreliosis or AD. Much is to be learned about the role of spirochetes in degenerative central nervous system disease.     

Tau Proteins and Tauopathies in Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by progressive memory loss and cognitive function deficits. There are two major pathological hallmarks that contribute to the pathogenesis of AD which are the presence of extracellular amyloid plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Despite extensive research that has been done on Aβ in the last two decades, therapies targeting Aβ were not very fruitful at treating AD as the efficacy of Aβ therapies observed in animal models is not reflected in human clinical trials. Hence, tau-directed therapies have received tremendous attention as the potential treatments for AD. Tauopathies are closely correlated with dementia and immunotherapy has been effective at reducing tau pathology and improving cognitive deficits in animal models. Thus, in this review article, we discussed the pathological mechanism of tau proteins, the key factors contributing to tauopathies, and therapeutic approaches for tauopathies in AD based on the recent progress in tau-based research.     

Icariin: A Potential Neuroprotective Agent in Alzheimer’s Disease and Parkinson’s Disease

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases worldwide. They are characterized by the loss of neurons and synapses in special parts of the central nervous system (CNS). There is no definitive treatment for AD and PD, but extensive studies are underway to identify the effective drugs which can slow the progression of these diseases by affecting the factors involved in their pathophysiology (i.e., aggregated proteins, neuroinflammation, and oxidative stress). Icariin, a natural compound isolated from Epimedii herba, is known because of its anti-inflammatory and anti-oxidant properties. In this regard, there are numerous studies indicating its potential as a natural compound against the progression of CNS disorders, such as neurodegenerative diseases. Therefore, this review aims to re-examine findings on the pharmacologic effects of icariin on factors involved in the pathophysiology of AD and PD.

     

Neuroinflammation,Gut Microbiome,and Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that develops insidiously and causes dementia finally. There are also clinical complications in advanced dementia, such as eating problems, infections, which will lead to the decline of patients’ life quality, and the rising cost of care for AD to our society. AD will be important public health challenge. Early detection of AD may be a key issue to prevent, delay, and stop the disease. Gut microbiome and neuroinflammation are closely related with nervous system diseases, although the specific mechanism is not clear. This review introduces the relationship between neuroinflammation, gut microbiome, and AD.     

Microglia Activation and Anti-inflammatory Regulation in Alzheimer’s Disease

Inflammatory regulators, including endogenous anti-inflammatory systems, can down-regulate inflammation thus providing negative feedback. Chronic inflammation can result from imbalance between levels of inflammatory mediators and regulators during immune responses. As a consequence, there are heightened inflammatory responses and irreversible tissue damage associated with many age-related chronic diseases. Alzheimer’s disease (AD) brain is marked by prominent inflammatory features, in which microglial activation is the driving force for the elaboration of an inflammatory cascade. How the regulation of inflammation loses its effectiveness during AD pathogenesis remains largely unclear. In this article, we will first review current knowledge of microglial activation and its association with AD pathology. We then discuss four examples of anti-inflammatory systems that could play a role in regulating microglial activation: CD200/CD200 receptor, vitamin D receptor, peroxisome proliferator-activated receptors, and soluble receptor for advanced glycation end products. Through this, we hope to illustrate the diverse aspects of inflammatory regulatory systems in brain and neurodegenerative diseases such as AD. We also propose the importance of neuronal defense systems, because they are part of the integral inflammatory and anti-inflammatory systems. Augmenting the anti-inflammatory defenses of neurons can be included in the strategy for restoration of balanced immune responses during aging and neurodegenerative diseases.