Alzheimer Disease: Friedlich AL

Rogers JT, Bush AI, Cho HH, Smith DH, Thomson AM, Friedlich AL, Lahiri DK, Leedman PJ, Huang X, Cahill CM. · Department of Psychiatry, Neurochemistry Laboratory, Massachusetts General Hospital, Charlestown, MA 02129, USA. · Biochem Soc Trans. · Pubmed #19021541 No free full text.

Abstract: The essential metals iron, zinc and copper deposit near the Abeta (amyloid beta-peptide) plaques in the brain cortex of AD (Alzheimer's disease) patients. Plaque-associated iron and zinc are in neurotoxic excess at 1 mM concentrations. APP (amyloid precursor protein) is a single transmembrane metalloprotein cleaved to generate the 40-42-amino-acid Abetas, which exhibit metal-catalysed neurotoxicity. In health, ubiquitous APP is cleaved in a non-amyloidogenic pathway within its Abeta domain to release the neuroprotective APP ectodomain, APP(s). To adapt and counteract metal-catalysed oxidative stress, as during reperfusion from stroke, iron and cytokines induce the translation of both APP and ferritin (an iron storage protein) by similar mechanisms. We reported that APP was regulated at the translational level by active IL (interleukin)-1 (IL-1-responsive acute box) and IRE (iron-responsive element) RNA stem-loops in the 5' untranslated region of APP mRNA. The APP IRE is homologous with the canonical IRE RNA stem-loop that binds the iron regulatory proteins (IRP1 and IRP2) to control intracellular iron homoeostasis by modulating ferritin mRNA translation and transferrin receptor mRNA stability. The APP IRE interacts with IRP1 (cytoplasmic cis-aconitase), whereas the canonical H-ferritin IRE RNA stem-loop binds to IRP2 in neural cell lines, and in human brain cortex tissue and in human blood lysates. The same constellation of RNA-binding proteins [IRP1/IRP2/poly(C) binding protein] control ferritin and APP translation with implications for the biology of metals in AD.

Puglielli L, Friedlich AL, Setchell KD, Nagano S, Opazo C, Cherny RA, Barnham KJ, Wade JD, Melov S, Kovacs DM, Bush AI. · Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA. · J Clin Invest. · Pubmed #16127459 links to  free full text

Abstract: 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.

Friedlich AL, Lee JY, van Groen T, Cherny RA, Volitakis I, Cole TB, Palmiter RD, Koh JY, Bush AI. · Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Massachusetts General Hospital, and Department of Psychiatry, Harvard Medical School, Charlestown, Massachusetts 02129-4404, USA. · J Neurosci. · Pubmed #15056725 links to  free full text

Abstract: Cerebral amyloid angiopathy (CAA) is common in Alzheimer's disease (AD) and may contribute to dementia and cerebral hemorrhage. Parenchymal beta-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 beta-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.

Perry G, Roder H, Nunomura A, Takeda A, Friedlich AL, Zhu X, Raina AK, Holbrook N, Siedlak SL, Harris PL, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. · Neuroreport. · Pubmed #10439473 No free full text.

Abstract: 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.