Presenilin-1 regulates the neuronal threshold to excitotoxicity both physiologically and pathologically

Grilli, Mariagrazia; Diodato, Enrica; Lozza, Gianluca; Brusa, Rossella; Casarini, María Jesús; Uberti, Daniela; Rozmahel, Richard; Westaway, David; George-Hyslop, Peter St; Memo, Maurizio; Ongini, Ennio

doi:10.1073/pnas.97.23.12822

Cited by 40 publications

(22 citation statements)

References 36 publications

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“…As expected, at 3 days after the injection, KA produced selective hippocampal cell loss in the CA3 subfield [17] (data not shown). The percentage of surviving neurons, as estimated by computer-assisted measurement of profile counts as an index of cell number, was about 55-60% of the corresponding saline-treated animals.…”

Section: Resultssupporting

confidence: 55%

“…After killing, brains were collected and fixed in Carnoy for 24 h. Coronal sections from paraffin-embedded tissue were cut at 5 mm and used for haematoxylin-eosin staining. Haematoxylin-eosin-positive undamaged neurons were counted in CA1, CA2, CA3 and DG hippocampal subfields by estimating the mean profile number/mm 2 , as described previously [17]. Some adjacent sections were incubated overnight with a polyclonal anti-Notch2 antiserum (1:30, Santa Cruz Biotechnology, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

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Long-lasting induction of Notch2 in the hippocampus of kainate-treated adult mice

Toninelli

Bernardi²,

Quarto³

et al. 2003

NeuroReport

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Notch proteins are involved in cell fate specification during development in tissues including brain. Little is known about their function in adulthood. Recently, Notch receptors have been hypothesized to play a role in neurodegeneration and in particular in Alzheimer's disease (Notch1) and CADASIL (Notch3). Here we show that another family member (Notch2) is constitutively expressed in adult mouse hippocampus in DG and not in CA1 and CA3 neurons. Treatment with kainic acid resulted in marked Notch2 induction in pyramidal neurons of CA1 and in a subpopulation of CA3 neurons surviving the lesion and protein expression was still detectable 6 weeks after drug treatment. These results suggest Notch2 involvement in the response of postmitotic neurons to excitotoxic stimuli.

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Section: Resultssupporting

confidence: 55%

Section: Methodsmentioning

confidence: 99%

Long-lasting induction of Notch2 in the hippocampus of kainate-treated adult mice

Toninelli

Bernardi²,

Quarto³

et al. 2003

NeuroReport

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“…Primary neurons overexpressing mutated PSEN-1 show increased vulnerability to excitotoxic damage. Accelerated neuronal death is also found in the hippocampus of mice overexpressing mutated PSEN-1 after KA induced excitotoxicity [95]. In comparison, mice with mutant PSEN-2 show decreased expression of cyclooxygenases COX-1 and COX-2 in the hippocampus, and reduced seizure activity after KA injury [96].…”

Section: Apoementioning

confidence: 80%

Slow Excitotoxicity in Alzheimer's Disease

Ong

Tanaka

Dawe

et al. 2013

JAD

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Abstract. Progress is being made in identifying possible pathogenic factors and novel genes in the development of Alzheimer's disease (AD). Many of these could contribute to 'slow excitotoxicity', defined as neuronal loss due to overexcitation as a consequence of decreased energy production due, for instance, to changes in insulin receptor signaling; or receptor abnormalities, such as tau-induced alterations in N-methyl-D-aspartate (NMDA) receptor phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate in a tonic, rather than a phasic manner. Moreover, in prodromal AD subjects, functional MRI reveals an increase in neural network activities relative to baseline, rather than loss of activity. This may be an attempt to compensate for reduced number of neurons, or reflect ongoing slow excitotoxicity. This article reviews possible links between AD pathogenic factors such as A␤PP/A␤ and tau; novel risk genes including clusterin, phosphatidylinositol-binding clathrin assembly protein, complement receptor 1, bridging integrator 1, ATP-binding cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin receptor A1; metabolic changes including insulin resistance and hypercholesterolemia; lipid changes including alterations in brain phospholipids, cholesterol and ceramides; glial changes affecting microglia and astrocytes; alterations in brain iron metallome and oxidative stress; and slow excitotoxicity. Better understanding of the possible molecular links between pathogenic factors and slow excitotoxicity could inform our understanding of the disease, and pave the way towards new therapeutic strategies for AD.

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“…12 Experimental animal models of cognitive impairment have demonstrated the presence of amyloid precursor protein in the area of ischemic damage. 13 Studies in mice overexpressing mutated presenilin 1 or presenilinknockout mice suggest that presenilin 1 mutations lead to enhanced neurodegeneration after focal ischemia or excitotoxicity. 9,14 This may suggest that mutations leading to higher levels of Aβ may increase the sensitivity to ischemia.…”

Section: Evidence From Experimental Studiesmentioning

confidence: 99%

Amyloid Burden, Neuroinflammation, and Links to Cognitive Decline After Ischemic Stroke

Thiel

Cechetto

Heiss

et al. 2014

Stroke

109

102

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O ne in 5 patients with stroke will end up demented shortly after a stroke, half with prior cognitive impairment and half without. After recurrent stroke, more than a third will become demented. 1 The mechanisms remain unclear beyond the fact that neurodegenerative and vascular mechanisms contribute to the cognitive decline.2 In this review, we explore experimental and clinical evidence of interaction between ischemia, amyloid deposition, and neuroinflammation and identify new potential therapeutic targets. Evidence From Experimental StudiesClinical data clearly indicate that the coexistence of stroke and Alzheimer disease (AD) leads to exacerbated dementia, 3 and experimental studies with animals have addressed the relationship between stroke and AD. [4][5][6][7][8][9] Although human studies have also indicated that soluble parenchymal amyloid precursor protein and β-amyloid 1 to 42 (Aβ 1-42 ) accumulate in patients with multi-infarct dementia, 10,11 there are animal studies examining neurodegenerative mechanisms and cognitive impairment in global and focal experimental ischemia. Changes in neurotransmitter systems, trophic factors, and cell signaling and neuroinflammatory mechanisms have been well documented.12 Experimental animal models of cognitive impairment have demonstrated the presence of amyloid precursor protein in the area of ischemic damage.13 Studies in mice overexpressing mutated presenilin 1 or presenilinknockout mice suggest that presenilin 1 mutations lead to enhanced neurodegeneration after focal ischemia or excitotoxicity. 9,14 This may suggest that mutations leading to higher levels of Aβ may increase the sensitivity to ischemia. In another study, mice overexpressing amyloid precursor protein with middle cerebral artery occlusion were shown to have enlarged infarcts and a stronger reduction of blood flow after the arterial occlusion.15 These experiments, however, also showed that the vasodilatory effect of the endothelium-dependent vasodilator acetylcholine was significantly reduced in transgenic mice, possibly suggesting that Aβ-induced disturbance in endothelium-dependent vascular reactivity may contribute to the higher ischemia sensitivity. Our research group has conducted several studies directly examining the pathological, neuroinflammatory, and behavioral relationship of stroke and AD in rat and mouse models. [4][5][6][7] In particular, these studies have focused on the potential synergism that would account for the clinical findings. A consequence of a chronic neuroinflammatory response is perturbation of the cerebrovascular system. Likewise, a perturbation of the cerebrovascular system will influence the degree of neuroinflammation after injury. A considerable body of evidence has demonstrated that AD is directly related to and has profound pathological changes in the cerebral microvasculature.16 Specific attention has recently focused on changes within brain endothelial cells in AD and in response to exposure to Aβ. 16 It has been hypothesized that during the onset of AD the breakdow...

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Presenilin-1 regulates the neuronal threshold to excitotoxicity both physiologically and pathologically

Cited by 40 publications

References 36 publications

Long-lasting induction of Notch2 in the hippocampus of kainate-treated adult mice

Long-lasting induction of Notch2 in the hippocampus of kainate-treated adult mice

Slow Excitotoxicity in Alzheimer's Disease

Amyloid Burden, Neuroinflammation, and Links to Cognitive Decline After Ischemic Stroke

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