Category Archives: 11-?? Hydroxylase

β-Secretase-1 (BACE1) is the rate-limiting enzyme for the genesis of amyloid-β

β-Secretase-1 (BACE1) is the rate-limiting enzyme for the genesis of amyloid-β (Aβ) peptides the main constituents of the amyloid plaques in the brains of Alzheimer’s disease (AD) patients. proteins in the brain with an emphasis on BACE1. We then address BACE1 elevation relative to amyloid plaque development KU 0060648 followed by updating recent understanding of a neurotrophic role of BACE1 in axon and synapse development. We further sophisticated the occurrence of axonal pathology in some other neurological conditions. Finally we propose pharmacological inhibition KU 0060648 of excessive BACE1 activity as an option to mitigate early axonal pathology occurring in AD and other neurological disorders. [94]. Besides AβPP BACE1 may proteolytically process a diverse array of substrates many of which appear to play a critical role in intercellular communication axonal guidance and myelination [82-85 87 93 95 96 The rich presence of BACE1 in presynaptic terminals allows this enzyme to execute an active role in synaptic development and plasticity presumably via its proteolytic modulation to AβPP and other substrates [11 26 36 91 92 Other data suggest that BACE1 may play a role in neuronal stress response and normal neuroplasticity. BACE1 is usually upregulated under nerve-racking conditions including ischemia hypoxia and traumatic injury [27 97 Oxidative stress and/or mitochondrial bioenergetic deficiency upregulate BACE1 expression and and indicate that neuronal activity potentiates synaptic Aβ release possibly via BACE1 upregulation [104 105 In the olfactory system blocking physiological activity by naris-occlusion enhances BACE1 mRNA and protein expression in neuronal somata and axonal terminals [37 92 106 This suggests a role for BACE1 in modulating synaptoplasticity during adulthood given that the primary olfactory pathway undergoes constant structural modulation regulated by experience [106]. SYNAPTIC AND AXONAL PATHOLOGY IN NEUROLOGICAL DISORDERS Synaptic and axonal lesions may contribute to pathogenesis and functional decline in many other neurological conditions in addition to AD [107]. TBI and TLE are probably the best analyzed KU 0060648 disorders with regards to the extent of axonal pathology [108-120]. TBI is usually associated with early and broad axonal pathology that can be anatomically detected by AβPP and Aβ antibodies [115-117]. BACE1 elevation has been also reported in dystrophic neurites in human TBI [68 69 Axonal pathology is usually a pathological feature of TLE mostly evidenced by the hippocampal mossy fiber sprouting [111-113]. Both TBI and TLE may be associated with brain amyloid pathology [68-70 116 Neuritic changes are a part of the neuropathology seen in PD and Lewy body dementia. Axonal spheroids and dystrophic neurites made up of α-synuclein and other protein aggregates are found in the cerebral cortex hippocampal formation and subcortical structures of PD brains [121-124]. As common AD (plaques and tangles) and PD (Lewy body KU 0060648 and neurites) pathologies may coexist in clinically diagnosed AD or PD patients (or aged individuals) [125] the possibility of α-synuclein colocalization with AβPP or BACE1 in dystrophic neurites is worth further investigation. For additional examples evidence suggests that axonal or neuritic pathology is usually associated with ischemic cerebral Ctcf stroke [112 113 and diabetic neuropathy [126]. Much work is needed to solution why axonal pathology occurs in various neurological disorders. Since there is loss of synaptic function in neurological diseases this pathology KU 0060648 may symbolize a part of neurodegenerative changes [107]. However the swelling/sprouting of axonal processes and presynaptic terminals may also implicate an aberrant regenerative phenomenon [53 55 Axonal and synaptic pathology could be linked to neuroplasticity a fundamental feature of the brain in response to internal and environmental stimuli. Early regenerative axonal and synaptic responses may serve a compensatory role to restore neuronal function whereas prolonged aberrant neuroplasticity could contribute to or exacerbate disease progression and functional loss [56 57 108 118 The molecular underpinning of axonal pathology is not clear KU 0060648 to date. Deficient axonal transport owing to dysfunctional protein trafficking and deregulation of the autophagy machinery may cause neuritic dystrophy and accumulation of intracellular organelles [59 127 Notably neuritic dystrophy can occur early or predominantly at the presynaptic sites without concurrently involving the axonal tract regions at least in some cases [10 36 66 This may be consistent with the notion that neuritic dystrophy may occur as a part of regenerative cellular attempts.