Cellular signaling roles of TGFβ, TNFα and βAPP in brain injury responses and Alzheimer's disease

Mattson, Mark P.; Barger, Steven W.; Furukawa, Koichi; Bruce, Annadora J.; Wyss‐Coray, Tony; Mark, Robert J.; Mucke, Lennart

doi:10.1016/s0165-0173(96)00014-8

Cited by 240 publications

(135 citation statements)

References 105 publications

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“…1D and F) and the pyramidal CA1 neurons (data not shown) of the rat hippocampus. Levels of TNF-a are found elevated in many neurological conditions in the brain including Alzheimer's and Parkinson's disease, stroke and ischemia, conditions known to be associated with memory deficits (Fiore et al, 1996;Mattson et al, 1997;Zaremba and Losy, 2001). Electrophysiological measurements taken from slices treated with TNF-a prior to HFS showed that it significantly inhibited LTP in the dentate gyrus (fEPSP 1169/10% 60 min post-tetanus, n0/ 9 compared to controls fEPSP 1859/9%, n 0/ 6; P B/0.001).…”

Section: Resultsmentioning

confidence: 99%

Methods of detection of the transcription factor NF-κB in rat hippocampal slices

Butler

Moynagh

O’Connor

2002

Journal of Neuroscience Methods

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The hippocampus is one of the most studied sites for understanding the cellular and molecular mechanisms underlying long-term potentiation (LTP) and long-term depression (LTD), mechanisms believed to underlie the formation and storage of memories. The early-phases of LTP and LTD have been most intensively studied and have been shown to involve the activation of several kinases and phosphatases, respectively. The factors involved in the later stages have largely yet to be elucidated. We have focused our attention on the transcription factor NF-kB as a possible factor involved in such late-phase processes, and have developed both immunocytochemistry and electrophoretic mobility shift assay (EMSA) to measure the activated forms of this factor. This is important as many of the studies in this area are performed in vitro and to our knowledge quantitative assessment has not previously being deemed feasible in slice work. The pro-inflammatory cytokines TNF-a and IL-1b both led to pronounced nuclear activation of NF-kB in the dentate granule cells as demonstrated by immunostaining and EMSA, respectively. Electrophysiological measurements taken from slices treated with TNF-a showed that it inhibited LTP (field excitatory post-synaptic potentials (fEPSP) 1169/10%, n 0/ 9, 60 min post-tetanus compared to control fEPSP 1859/9%, n 0/ 6; P B/0.001). The neurotransmitter L-glutamate also led to activation of NF-kB and electrophysiology recordings showed a small but sustained increase in synaptic transmission (fEPSP 1069/12%, 30 min post-drug). These methods provide valuable tools to forward our understanding of the role of NF-kB in plasticity as well as in many neurological disorders being mimicked by in vitro studies. #

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Section: Resultsmentioning

confidence: 99%

Methods of detection of the transcription factor NF-κB in rat hippocampal slices

Butler

Moynagh

O’Connor

2002

Journal of Neuroscience Methods

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“…Several lines of evidence indicate that through the a-secretase pathway, APP is cleaved within the sequence of the Ab peptide and generates the sAPPa fragment (Esch et al, 1990), which is beneficial for neuronal survival (Mattson et al, 1997;Wallace et al, 1997), whereas through the b-secretase pathway, APP is cleaved to form neurotoxic Ab and is involved in the pathogenesis of AD (Haass et al, 1992;Shoji et al, 1992;Bodles and Barger, 2005). Interestingly, the widely used AChE inhibitors, including donepezil, rivastigmine, and galantamine, have been shown to increase sAPPa release (Racchi et al, 2004).…”

Section: Hupa Regulates the Processing Of App To The Nonamyloidogenicmentioning

confidence: 99%

Huperzine A Activates Wnt/β-Catenin Signaling and Enhances the Nonamyloidogenic Pathway in an Alzheimer Transgenic Mouse Model

Wang

Zheng

Wang

et al. 2011

Neuropsychopharmacol

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Huperzine A (HupA) is a reversible and selective inhibitor of acetylcholinesterase (AChE), and it has multiple targets when used for Alzheimer's disease (AD) therapy. In this study, we searched for new mechanisms by which HupA could activate Wnt signaling and reduce amyloidosis in AD brain. A nasal gel containing HupA was prepared. No obvious toxicity of intranasal administration of HupA was found in mice. HupA was administered intranasally to b-amyloid (Ab) precursor protein and presenilin-1 double-transgenic mice for 4 months. We observed an increase in ADAM10 and a decrease in BACE1 and APP695 protein levels and, subsequently, a reduction in Ab levels and Ab burden were present in HupA-treated mouse brain, suggesting that HupA enhances the nonamyloidogenic APP cleavage pathway. Importantly, our results further showed that HupA inhibited GSK3a/b activity, and enhanced the b-catenin level in the transgenic mouse brain and in SH-SY5Y cells overexpressing Swedish mutation APP, suggesting that the neuroprotective effect of HupA is not related simply to its AChE inhibition and antioxidation, but also involves other mechanisms, including targeting of the Wnt/b-catenin signaling pathway in AD brain.

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“…The toxic effects of A␤ oligomers include synaptic structural deterioration (7,8) and functional deficits such as inhibition of synaptic transmission (9) and synaptic plasticity (10 -13), as well as memory loss (11,14,15). Accumulation of high levels of these oligomers may also trigger inflammatory processes and oxidative stress in the brain probably due to activation of astrocytes and microglia (16,17). Thus, to understand how a physiologically produced peptide becomes a misfolded toxin has been one of the key issues in uncovering the molecular pathogenesis of the disease.…”

mentioning

confidence: 99%

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

Zhao

Lacor

Chen

et al. 2009

Journal of Biological Chemistry

143

101

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Accumulation of amyloid ␤ (A␤) oligomers in the brain is toxic to synapses and may play an important role in memory loss in Alzheimer disease. However, how these toxins are built up in the brain is not understood. In this study we investigate whether impairments of insulin and insulin-like growth factor-1 (IGF-1) receptors play a role in aggregation of A␤. Using primary neuronal culture and immortal cell line models, we show that expression of normal insulin or IGF-1 receptors confers cells with abilities to reduce exogenously applied A␤ oligomers (also known as ADDLs) to monomers. In contrast, transfection of malfunctioning human insulin receptor mutants, identified originally from patient with insulin resistance syndrome, or inhibition of insulin and IGF-1 receptors via pharmacological reagents increases ADDL levels by exacerbating their aggregation. In healthy cells, activation of insulin and IGF-1 receptor reduces the extracellular ADDLs applied to cells via seemingly the insulin-degrading enzyme activity. Although insulin triggers ADDL internalization, IGF-1 appears to keep ADDLs on the cell surface. Nevertheless, both insulin and IGF-1 reduce ADDL binding, protect synapses from ADDL synaptotoxic effects, and prevent the ADDL-induced surface insulin receptor loss. Our results suggest that dysfunctions of brain insulin and IGF-1 receptors contribute to A␤ aggregation and subsequent synaptic loss.Abnormal protein misfolding and aggregation are common features in neurodegenerative diseases such as Alzheimer (AD), 2 Parkinson, Huntington, and prion diseases (1-3). In the AD brain, intracellular accumulation of hyperphosphorylated Tau aggregates and extracellular amyloid deposits comprise the two major pathological hallmarks of the disease (1, 4). A␤ aggregation has been shown to initiate from A␤1-42, a peptide normally cleaved from the amyloid precursor protein (APP) via activities of ␣-and ␥-secretases (5, 6). A large body of evidence in the past decade has indicated that accumulated soluble oligomers of A␤1-42, likely the earliest or intermediate forms of A␤ deposition, are potently toxic to neurons. The toxic effects of A␤ oligomers include synaptic structural deterioration (7,8) and functional deficits such as inhibition of synaptic transmission (9) and synaptic plasticity (10 -13), as well as memory loss (11,14,15). Accumulation of high levels of these oligomers may also trigger inflammatory processes and oxidative stress in the brain probably due to activation of astrocytes and microglia (16,17). Thus, to understand how a physiologically produced peptide becomes a misfolded toxin has been one of the key issues in uncovering the molecular pathogenesis of the disease.A␤ accumulation and aggregation could derive from overproduction or impaired clearance. Mutations of APP or presenilins 1 and 2, for example, are shown to cause overproduction of A␤1-42 and amyloid deposits in the brain of early onset AD (18,19). Because early onset AD accounts for less than 5% of entire AD population, APP and presenilin mutati...

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Cellular signaling roles of TGFβ, TNFα and βAPP in brain injury responses and Alzheimer's disease

Cited by 240 publications

References 105 publications

Methods of detection of the transcription factor NF-κB in rat hippocampal slices

Methods of detection of the transcription factor NF-κB in rat hippocampal slices

Huperzine A Activates Wnt/β-Catenin Signaling and Enhances the Nonamyloidogenic Pathway in an Alzheimer Transgenic Mouse Model

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

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