Avi L. Friedlich

Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation

Responses to increased oxidative stress may be the common mechanism responsible for the varied cytopathology of Alzheimer disease (AD). A possible link in support of this hypothesis is that one of the most striking features of AD, the abnormal accumulation of highly phosphorylated tau and neurofilament proteins, may be brought about by extracellular receptor kinase (ERK) whose activation is a common response to oxidative stress. In this study, we demonstrate that activated ERK is specifically increased in the same vulnerable neurons in AD that are the site of oxidative damage and abnormal phosphorylation. These findings suggest that ERK dysregulation, likley resulting from oxidative stress, could play an important role in the increased phosphorylation of cytoskeletal proteins observed in AD.

Alzheimer disease β-amyloid activity mimics cholesterol oxidase

The abnormal accumulation of amyloid beta-peptide (Abeta) in the form of senile (or amyloid) plaques is one of the main characteristics of Alzheimer disease (AD). Both cholesterol and Cu2+ have been implicated in AD pathogenesis and plaque formation. Abeta binds Cu2+ with very high affinity, forming a redox-active complex that catalyzes H2O2 production from O2 and cholesterol. Here we show that Abeta:Cu2+ complexes oxidize cholesterol selectively at the C-3 hydroxyl group, catalytically producing 4-cholesten-3-one and therefore mimicking the activity of cholesterol oxidase, which is implicated in cardiovascular disease. Abeta toxicity in neuronal cultures correlated with this activity, which was inhibited by Cu2+ chelators including clioquinol. Cell death induced by staurosporine or H2O2 did not elevate 4-cholesten-3-one levels. Brain tissue from AD subjects had 98% more 4-cholesten-3-one than tissue from age-matched control subjects. We observed a similar increase in the brains of Tg2576 transgenic mice compared with nontransgenic littermates; the increase was inhibited by in vivo treatment with clioquinol, which suggests that brain Abeta accumulation elevates 4-cholesten-3-one levels in AD. Cu2+-mediated oxidation of cholesterol may be a pathogenic mechanism common to atherosclerosis and AD.

Neuronal Zinc Exchange with the Blood Vessel Wall Promotes Cerebral Amyloid Angiopathy in an Animal Model of Alzheimer's Disease

Cerebral amyloid angiopathy (CAA) is common in Alzheimers disease (AD) and may contribute to dementia and cerebral hemorrhage. Parenchymal β-amyloid deposition is dependent on the activity of zinc transporter 3 (ZnT3), a neocortical synaptic vesicle membrane protein that causes enrichment of exchangeable Zn2+ in the vesicle, which is externalized on neurotransmission. However, the contribution of zinc to vascular β-amyloid deposition remains unclear. Here, we identify for the first time an exchangeable pool of Zn2+ in the cerebrovascular wall of normal mice. This histochemically reactive Zn2+ is enriched in CAA in a transgenic mouse model of AD (Tg2576), and a dramatic reduction of CAA occurs after targeted disruption of the Znt3 gene in these mice. Also, in Znt3 knock-out mice, the amount of exchangeable Zn2+ [detected by N-(6-methoxy-8-quinolyl)-p-carboxybenzoylsulphonamide (TFL-Zn)] in the perivascular space was significantly decreased in the neocortex but not in peripheral organs. ZnT3 was not detected in the cerebral vessel walls or in blood components of wild-type mice. Thus, synaptic ZnT3 activity may promote CAA by indirectly raising exchangeable Zn2+ concentrations in the perivascular spaces of the brain.

The 5′-untranslated region of Parkinson's disease α -synuclein messengerRNA contains a predicted iron responsive element

The 5′-untranslated region of Parkinsons disease α -synuclein messengerRNA contains a predicted iron responsive element

Oxidative Stress in Parkinson’s Disease

Parkinson’s disease (PD) is a progressive, age-related movement disorder, whose neuropathology is characterized by degeneration of the afferent pigmented neurons of the substantia nigra. Also associated with PD neuropathology are disrupted iron homeostasis, oxidative stress, and intracellular deposition of alpha-synuclein protein in Lewy bodies. Here we review oxidative stress mechanisms in Parkinson’s disease, with emphasis on the relationship between oxidative stress and alpha-synuclein gene expression.

Neocortical levels of lithium are increased in bipolar disorder

Salts of lithium, present in the human diet at trace levels,1 are used to manage depressive, manic and psychotic symptoms in bipolar disorder and related conditions.2, 3 Although a neurological function for lithium was first proposed over 60 years ago based on its anti-manic properties,2 surprisingly, a significant pool of lithium has never been identified in the brain.4, 5 In this study, with quadrupole inductively coupled plasma-mass spectroscopy, lithium is identified as a physiological trace element in the human neocortex. Moreover, cortical levels of lithium are found to be elevated in bipolar subjects with no past history of lithium pharmacotherapy.

Treatment advances in Alzheimer's disease based on the oxidative stress model.

Effective therapy for Alzheimers disease (AD), up to this point, has been hampered by our inability to diagnose the disease in its early stages, before the occurrence of significant neurodegeneration and clinical symptoms. Because AD historically has been defined by neuropathologic criteria, treatment strategies have been aimed at diminishing the pathologic end result of the disease process, namely neurodegenerative changes associated with extracellular amyloid-beta-containing plaques, as well as intracellular neurofibrillary tangles of the hyper-phosphorylated microtubule protein, tau. While these avenues continue to be pursued, results thus far have been disappointing. It is now understood that oxidative stress plays a key role in the shared pathophysiology of neurodegenerative diseases and aging. For experimental treatment of AD, the focus of research and development efforts is increasingly shifting to target mechanisms of oxidative stress. Most recently, dimebon, whose mechanism of action relates to improved mitochondrial function, has emerged as a promising candidate for experimental treatment of AD.

Copper, Zinc, and Alzheimer’s Disease

Current knowledge of the factors regulating total body and brain-specific Cu and Zn metabolism is surveyed. With special reference to s-amyloid, evidence is then presented for altered Cu or Zn metabolism or physiology in Alzheimer’s disease, the major age-dependent cause of memory loss in man. Altered Cu and Zn metabolism or physiology in AD is likely to be directly coupled to pathogenesis, but may not be directly linked to diet.