This chapter discusses the role of alpha-syn in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Alzheimer's disease (AD) is among the most common ...neurodegenerative disorders in Europe and the US and is the leading cause of dementia in the aging population. Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by bradykinesia, resting tremor, postural instability and autonomic features. Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that typically affects patient 50 years of age or above. Since accumulation of alpha-syn oligomers is viewed as being key to the neurodegenerative process, methods aimed at reducing alpha-syn oligomers, either by reducing alpha-syn synthesis or aggregation or by increasing the clearance of alpha-syn, have been proposed as viable therapeutic approaches.
Considerable advances have been made in the past years in developing novel experimental models of neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), ...Fronto-Temporal Dementias (FTD), Amyotrophic Lateral Sclerosis (ALS), and trinucleotide repeat disorders (TNRDs). The main postulate of several of the genetically modified murine models of neurodegenerative disorders is that a single molecular alteration might trigger a cascade of events that eventually will result in the full spectrum of the clinicopathological alterations observed in human disease. Therefore, overexpression of mutant proteins in transgenic (tg) mice might mimic some aspects associated with the gain of a toxic function, while targeted deletion of selected genes might mimic aspects associated with loss of a trophic or protective function. To date, several genes have been identified to be associated with familial forms of AD, PD, FTD, ALS, and TNRDs. Single or combined tg and knockout models targeting most of these genes have been developed that recapitulate one or several aspects of each disorder. In these models, abnormal accumulation and misfolding (toxic conversion) of endogenous proteins is being extensively explored as a key pathogenic event leading to neurodegeneration. Thus, the main focus of this chapter is to provide a perspective as to the efforts in developing genetically engineered models of the most common neurodegenerative disorders. Further development and investigation of animal models of these diseases holds the promise of better understanding their pathogenesis and discovering and testing new treatments.
Alzheimer’s disease (AD) is a leading cause of dementia in the aging population. This progressive neurodegenerative disorder is characterized neuropathologically by the presence of plaques composed ...of amyloid-β (Aβ) peptides and neurofibrillary tangles containing phosphorylated τ however, neurodegeneration in AD probably initiates with damage to the synaptic terminal. In addition to the neurodegenerative features of AD, the pathological process in this disorder is accompanied by significant alterations in adult neurogenesis in the hippocampus. Although the precise mechanisms leading to neurodegeneration and neurogenic alterations in AD are not completely understood, several lines of investigation indicate that enzymatic cleavage of Aβ may play an important role in preventing or reversing the neurodegenerative process in AD. Neprilysin (NEP) is one such Aβ-degrading enzyme, and in addition to its Aβ-dependent effects, NEP is capable of promoting neurogenesis and synaptic remodeling. Since this endopeptidase is capable of cleaving a wide range of neuropeptides with neurotrophic activity, its trophic action in the CNS is probably related to enzymatic processing of substrates such as neuropeptide Y (NPY) that results in the generation of neuroactive products. Thus, NEP represents a unique example of a proteolytic enzyme with dual action: degradation (Aβ) and processing (NPY); both actions are neuroprotective. Therefore, understanding the effects of NEP on NPY and other neuropeptides might provide new information about the neuroprotective mechanisms of NEP in the mature CNS and in animal models of AD.
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