APP as a Protective Factor in Acute Neuronal Insults

Hefter, Dimitri; Draguhn, Andreas

doi:10.3389/fnmol.2017.00022

Cited by 72 publications

(62 citation statements)

References 223 publications

(273 reference statements)

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“…Importantly, this finding was not causally related to endocrine status because both wt and arcAβ mice responded similarly to an acute stressful challenge. How Aβ oligomers or other aspects of the hAPParc/swe genotype modulate the impact of stress is worth investigating in the future, but one possible explanation may be provided by Aβ itself: in its physiological role, Aβ has synapto‐protective effects and is generated in response to excitatory stress, such as after physical impact, ischaemia or chronic stress (Giuffrida et al., ; Hefter & Draguhn, ; Hick et al., ; Kögel, Deller, & Behl, ; Palop & Mucke, ; Roselli, ). Thus, abundant, but not excessive, Aβ oligomers in young arcAβ mice may have protected post‐synaptic synapses from overexcitation, and subsequent downregulation, by chronic stress, preventing attentional decline.…”

Section: Discussionmentioning

confidence: 99%

The Arctic/Swedish APP mutation alters the impact of chronic stress on cognition in mice

Cortese

Delgado-Morales

Almeida

et al. 2019

Eur J of Neuroscience

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Chronic stress is a major risk factor for developing Alzheimer's disease (AD) and promotes the processing of amyloid precursor protein (APP) to β‐amyloid (Aβ). However, the precise relationship of stress and disease‐typical cognitive decline is presently not well understood. The aim of this study was to investigate how early life stress may affect cognition in adult mice with and without soluble Aβ pathology typical for the early stages of the disease. We focussed on sustained attention and response control, aspects of cognition mediated by the prefrontal cortex that are consistently impaired both in early AD and after chronic stress exposure. Young wild‐type mice as well as transgenic arcAβ mice overexpressing the hAPParc/swe transgene were exposed to a chronic unpredictable stress paradigm (age 3–8 weeks). At 15 weeks, these mice were tested on the 5‐choice serial reaction time task, a test of sustained attention and executive control. We found that, expectedly, chronic stress increased impulsive choices and impaired sustained attention in wild‐type mice. However, the same treatment reduced impulsivity and did not interfere with sustained attention in arcAβ mice. These findings suggest an unexpected interaction between chronic stress and Aβ whereby Aβ‐pathology caused by the hAPParc/swe mutation prevented and/or reversed stress‐induced cognitive changes through mechanisms that deserve further investigation. They also indicate that Aβ, in modest amounts, may have a beneficial role for cognitive stability, for example by protecting neural networks from the impact of further physiological or behavioural stress.

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Section: Discussionmentioning

confidence: 99%

The Arctic/Swedish APP mutation alters the impact of chronic stress on cognition in mice

Cortese

Delgado-Morales

Almeida

et al. 2019

Eur J of Neuroscience

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“…Indeed, APP participates in a number of important functions in the brain, including synaptic function and cellular response to stress (Panegyres ). Numerous studies have suggested that APP is a neuroprotective factor in acute neuronal insults, including acute hypoxia‐ischemia, traumatic brain injury and excitotoxicity (Hefter and Draguhn ). Our data demonstrated that MCAO induced evident decrease in APP level compared with the sham‐control at 6 h, whereas Tan‐67 treatment attenuated MCAO‐induced APP decrease and this effect could be reversed by naltrindole.…”

Section: Discussionmentioning

confidence: 99%

“…Despite its key role in the molecular neuropathology of AD, increasing evidence indicate that APP is a neuroprotective factor in acute ischemic stroke (Hefter and Draguhn 2017). On the other hand, ischemic stroke also alters APP expression and processing (Hiltunen et al 2009).…”

mentioning

confidence: 99%

The non‐peptidic δ‐opioid receptor agonist Tan‐67 mediates neuroprotection post‐ischemically and is associated with altered amyloid precursor protein expression, maturation and processing in mice

Min

Wang

et al. 2017

Journal of Neurochemistry

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Tan-67 is a selective non-peptidic δ-opioid receptor (DOR) agonist that confers neuroprotection against cerebral ischemia/reperfusion (I/R)-caused neuronal injury in pre-treated animals. In this study, we examined whether post-ischemic administration of Tan-67 in stroke mice is also neuroprotective and whether the treatment affects expression, maturation and processing of the amyloid precursor protein (APP). A focal cerebral I/R model in mice was induced by middle cerebral artery occlusion for 1 h and Tan-67 (1.5, 3 or 4.5 mg/kg) was administered via the tail vein at 1 h after reperfusion. Alternatively, naltrindole, a selective DOR antagonist (5 mg/kg), was administered 1 h before Tan-67 treatment. Our results showed that post-ischemic administration of Tan-67 (3 mg/kg or 4.5 mg/kg) was neuroprotective as shown by decreased infarct volume and neuronal loss following I/R. Importantly, Tan-67 improved animal survival and neurobehavioral outcomes. Conversely, naltrindole abolished Tan-67 neuroprotection in infarct volume. Tan-67 treatment also increased APP expression, maturation and processing in the ipsilateral penumbral area at 6 h but decreased APP expression and maturation in the same brain area at 24 h after I/R. Tan-67-induced increase in APP expression was also seen in the ischemic cortex at 24 h following I/R. Moreover, Tan-67 attenuated BACE-1 expression, β-secretase activity and the BACE cleavage of APP in the ischemic cortex at 24 h after I/R, which was abolished by naltrindole. Our data suggest that Tan-67 is a promising DOR-dependent therapeutic agent for treating I/R-caused disorder and that Tan-67-mediated neuroprotection may be mediated via modulating APP expression, maturation and processing, despite an uncertain causative relationship between the altered APP and the outcomes observed.

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“…APP is a single‐pass transmembrane, highly pleiotropic protein involved in numerous cellular functions, such as iron transport, cell and synaptic adhesion, homeostasis, and apoptosis . APP is ubiquitously expressed as multiple splice variants, which undergo extensive post‐translational modification .…”

Section: Introductionmentioning

confidence: 99%

“…APP is a single-pass transmembrane, highly pleiotropic protein involved in numerous cellular functions, such as iron transport, cell and synaptic adhesion, homeostasis, and apoptosis. [6][7][8] APP is ubiquitously expressed as multiple splice variants, which undergo extensive post-translational modification. 9 Deposition of amyloid b peptide, a proteolytic product of APP, in senile plaques and in the walls of cerebral blood vessels is a hallmark of Alzheimer's disease.…”

Section: Introductionmentioning

confidence: 99%

Amyloid precursor protein is overexpressed in bladder cancer and contributes to the malignant bladder cancer cell behaviors

Zhang

Zhou

et al. 2018

Int J of Urology

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APP as a Protective Factor in Acute Neuronal Insults

Cited by 72 publications

References 223 publications

The Arctic/Swedish APP mutation alters the impact of chronic stress on cognition in mice

The Arctic/Swedish APP mutation alters the impact of chronic stress on cognition in mice

The non‐peptidic δ‐opioid receptor agonist Tan‐67 mediates neuroprotection post‐ischemically and is associated with altered amyloid precursor protein expression, maturation and processing in mice

Amyloid precursor protein is overexpressed in bladder cancer and contributes to the malignant bladder cancer cell behaviors

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