Amyloid hypothesis, synaptic function, and Alzheimer’s disease, or: Beware: the dogma is revitalized
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Amyloid (mycology)
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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.
Amyloid (mycology)
Neuropathology
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Amyloid (mycology)
β amyloid
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Alzheimer’s disease is an aging related disorder of the mind, accountable for 60-80 percent of all cases of dementia. With its insidious progression and the decline of cognitive abilities, this disease is a major challenge for our society as a whole. This is because of the growing proportion of people living to advanced age and our current lack of capacity to prevent or even give effective symptomatic treatments to the disorder. At the advanced stages of the disease the patient is more or less completely dependent upon help from caregivers and family placing a huge stress on both society and the patient’s next of kin.Alzheimer’s disease is characterized by two cardinal pathological lesions. First, the senile plaques, consisting of β-amyloid, and second, the neurofibrillary tangles consisting of Tau. While most Alzheimer’s disease cases have an unknown etiology there are cases of familial Alzheimer’s disease, where a single mutated gene gives rise to the disease, typically with an early onset of symptoms. These disease related mutations all point to a critical role of the peptide β-amyloid and the processing of its precursor protein, the amyloid precursor protein (APP). While β-amyloid and APP have been studied extensively for almost three decades, we still require more knowledge of their normal roles in the brain.Multiple lines of evidence implicates synapses as early and critical sites of β-amyloid and APP function and dysfunction. The loss of synaptic terminals remainsthe best pathological correlate of the cognitive decline in Alzheimer’s disease.In this thesis, on the nature of β-amyloid, we set out to investigate some of the roles β-amyloid and APP play at synapses, both in normal physiology and disease. We found that depletion of APP leads to alterations in synaptic composition andneuronal morphology. We showed that β-amyloid aggregates even before theappearance of plaques and that this concurs with the disappearance of a 20 kDputative tetramer in brains of Alzheimer’s disease model transgenic mice.Moreover, we investigated the effects of two familial Alzheimer’s disease mutations on synaptic proteins in hippocampal spheroids generated from induced pluripotent stem cells (iPSCs) from patients and healthy gender matched controls. We found that many of the changes between Alzheimer’s disease hippocampal spheroids and normal samples were in synaptic proteins. The final study focuses on the effects of β-amyloid on neuronal hyper-excitability, an increasingly highlighted early feature in Alzheimer’s disease that is also recapitulated in animal models of the disease. We describe specific effects of β-amyloid on cortical CaMKII positive neurons, increasing both firing frequency and amplitude of these cells, highlighting that β-amyloid targeting of CaMKII positive synapses might contribute to the hyperexcitability that is increasingly viewed as an early feature in Alzheimer’s disease.Taken together this work describes and attempts to explain important roles that β-amyloid and APP play at synapses, with implications both for health and disease.
Amyloid (mycology)
Cognitive Decline
Etiology
Tau protein
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Pathogenesis
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In 1887, S.A. Belyakov, a physician of the Imperial Medical and Surgical Academy, first described amyloid deposits in the brain of patients with dementia. Later, in 1906, A. Alzheimer revealed amyloid plaques and tau tangles in a patient with clinical signs of dementia. Over the following 100 years, the development of the concept of the amyloid origin of Alzheimer's disease (AD) confirmed numerous relationships between the brain accumulation of APs and cognitive decline. And if at the beginning of the amyloid era many researchers considered that the disease was caused by amyloid beta (Aβ) protein overproduction, in recent years they have increasingly pointed to a defect in the mechanisms of Aβ clearance, especially after the discovery of the lymphatic system of the brain. The role of disturbed homeostasis of redox-active metals, primarily iron and copper, in the development of the disease is also considered. The amyloid hypothesis of AD has served as the basis for several areas in the design of drugs, such as secretase inhibitors, immunomodulatory drugs for active and passive immunization. However, only one drug (Akatinol memantine, an inhibitor of NMDA receptors and glutamatergic excitotoxicity) for the treatment of AD has been introduced into clinical practice over the past 20 years. Of interest are the data obtained in new studies of Akatinol memantine, which suggest that the latter is able to some extent affect the main pathophysiological processes underlying the development of cognitive impairment in Alzheimer-type pathology.
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Amyloid (mycology)
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Cognitive Decline
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beta-Amyloid peptide accumulation plays a central role in the pathogenesis of Alzheimer's disease. Aberrant beta-amyloid buildup in the brain has been shown to be present both in the extracellular space and within neurons. Synapses are important targets of beta-amyloid, and alterations in synapses better correlate with cognitive impairment than amyloid plaques or neurofibrillary tangles. The link between beta-amyloid and synapses became even tighter when it was discovered that beta-amyloid accumulates within synapses and that synaptic activity modulates beta-amyloid secretion. Currently, a central question in Alzheimer's disease research is what role synaptic activity plays in the disease process, and how specifically beta-amyloid is involved in the synaptic dysfunction that characterizes the disease.
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