Familial Alzheimer’s disease presenilin-2 mutants affect Ca2+ homeostasis and brain network excitability

Pendin, Diana; Fasolato, Cristina; Basso, Emy; Filadi, Riccardo; Greotti, Elisa; Galla, Luisa; Gomiero, Chiara; Leparulo, Alessandro; Redolfi, Nelly; Scremin, Elena; Vajente, Nicola; Pozzan, Tullio; Pizzo, Paola

doi:10.1007/s40520-019-01341-0

Cited by 8 publications

(8 citation statements)

References 15 publications

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“…From a molecular point of view, these defects are likely caused by the initial surge of intraneuronal Aβ accumulation and by the late extracellular Aβ deposition. Nonetheless, a comparison with the PS2.30H line that does not accumulate Aβ highlights Aβ-independent effects, which are linked to the PS2 mutation [65]. Moreover, their absence in PS2KO mice suggests that PS2.30H mice are dominated by gain effects rather than loss-of-function, contrary to what was previously suggested [34].…”

Section: Molecular and Cellular Pathways Involved In So Changesmentioning

confidence: 66%

“…Moreover, their absence in PS2KO mice suggests that PS2.30H mice are dominated by gain effects rather than loss-of-function, contrary to what was previously suggested [34]. Regarding the molecular aspects linked to the PS2 mutation, we are aware of alterations in Ca 2+ homeostasis and metabolic pathways, as well as in autophagic steps, all of which are relevant issues from a pathogenic perspective of AD [32,[65][66][67][68][69][70][71]. In particular, we cannot exclude that some of the observed defects are linked to alterations in Notch signaling, even if Notch is a major substrate of PS1 rather than PS2 [34].…”

Section: Molecular and Cellular Pathways Involved In So Changesmentioning

confidence: 83%

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Dampened Slow Oscillation Connectivity Anticipates Amyloid Deposition in the PS2APP Mouse Model of Alzheimer’s Disease

Leparulo

Mahmud

Scremin

et al. 2019

Cells

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To fight Alzheimer’s disease (AD), we should know when, where, and how brain network dysfunctions initiate. In AD mouse models, relevant information can be derived from brain electrical activity. With a multi-site linear probe, we recorded local field potentials simultaneously at the posterior-parietal cortex and hippocampus of wild-type and double transgenic AD mice, under anesthesia. We focused on PS2APP (B6.152H) mice carrying both presenilin-2 (PS2) and amyloid precursor protein (APP) mutations, at three and six months of age, before and after plaque deposition respectively. To highlight defects linked to either the PS2 or APP mutation, we included in the analysis age-matched PS2.30H and APP-Swedish mice, carrying each of the mutations individually. Our study also included PSEN2−/− mice. At three months, only predeposition B6.152H mice show a reduction in the functional connectivity of slow oscillations (SO) and in the power ratio between SO and delta waves. At six months, plaque-seeding B6.152H mice undergo a worsening of the low/high frequency power imbalance and show a massive loss of cortico-hippocampal phase-amplitude coupling (PAC) between SO and higher frequencies, a feature shared with amyloid-free PS2.30H mice. We conclude that the PS2 mutation is sufficient to impair SO PAC and accelerate network dysfunctions in amyloid-accumulating mice.

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Section: Molecular and Cellular Pathways Involved In So Changesmentioning

confidence: 66%

Section: Molecular and Cellular Pathways Involved In So Changesmentioning

confidence: 83%

Dampened Slow Oscillation Connectivity Anticipates Amyloid Deposition in the PS2APP Mouse Model of Alzheimer’s Disease

Leparulo

Mahmud

Scremin

et al. 2019

Cells

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“…As mentioned above, FAD-PS2 mutants reduce ER Ca 2+ content and the cytosolic Ca 2+ rise induced by stimuli that cause Ca 2+ store depletion [60,129,148,[151][152][153]159,162,163] (Figure 1). This effect is due to the capacity of the protein to interfere with SERCA activity, partially blocking it [162].…”

Section: Presenilin 2 and Ca 2+ Homeostasismentioning

confidence: 66%

“…Moreover, in primary neurons from B6.152H tg mice, cell bioenergetics was also significantly affected [178]. Finally, the Ca 2+ hyperactivity described in both FAD-PS2 mouse models likely contributes to the hyper-excitability found at the brain network level in adult, anesthetized animals, in the presence or absence of Aβ accumulation [163,179,180].…”

Section: Presenilin 2 and Ca 2+ Homeostasismentioning

confidence: 86%

Intracellular Calcium Dysregulation by the Alzheimer’s Disease-Linked Protein Presenilin 2

Galla

Redolfi

Pozzan

et al. 2020

IJMS

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Alzheimer’s disease (AD) is the most common form of dementia. Even though most AD cases are sporadic, a small percentage is familial due to autosomal dominant mutations in amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes. AD mutations contribute to the generation of toxic amyloid β (Aβ) peptides and the formation of cerebral plaques, leading to the formulation of the amyloid cascade hypothesis for AD pathogenesis. Many drugs have been developed to inhibit this pathway but all these approaches currently failed, raising the need to find additional pathogenic mechanisms. Alterations in cellular calcium (Ca2+) signaling have also been reported as causative of neurodegeneration. Interestingly, Aβ peptides, mutated presenilin-1 (PS1), and presenilin-2 (PS2) variously lead to modifications in Ca2+ homeostasis. In this contribution, we focus on PS2, summarizing how AD-linked PS2 mutants alter multiple Ca2+ pathways and the functional consequences of this Ca2+ dysregulation in AD pathogenesis.

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“…The PS1 mutant (mPS1) results in impaired lysosomal acidification and reduced autophagic degradation. In fact, genetic mutations of PS1 and PS2 are associated with the pathogenesis of AD as demonstrated in the familial autosomal dominant AD [ 92 , 93 , 94 , 95 ].…”

Section: Autophagy and Nddsmentioning

confidence: 99%

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

Luo

Sandhu

Rungratanawanich

et al. 2020

IJMS

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With aging, the nervous system gradually undergoes degeneration. Increased oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and cell death are considered to be common pathophysiological mechanisms of various neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), organophosphate-induced delayed neuropathy (OPIDN), and amyotrophic lateral sclerosis (ALS). Autophagy is a cellular basic metabolic process that degrades the aggregated or misfolded proteins and abnormal organelles in cells. The abnormal regulation of neuronal autophagy is accompanied by the accumulation and deposition of irregular proteins, leading to changes in neuron homeostasis and neurodegeneration. Autophagy exhibits both a protective mechanism and a damage pathway related to programmed cell death. Because of its “double-edged sword”, autophagy plays an important role in neurological damage and NDDs including AD, PD, HD, OPIDN, and ALS. Melatonin is a neuroendocrine hormone mainly synthesized in the pineal gland and exhibits a wide range of biological functions, such as sleep control, regulating circadian rhythm, immune enhancement, metabolism regulation, antioxidant, anti-aging, and anti-tumor effects. It can prevent cell death, reduce inflammation, block calcium channels, etc. In this review, we briefly discuss the neuroprotective role of melatonin against various NDDs via regulating autophagy, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.

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Familial Alzheimer’s disease presenilin-2 mutants affect Ca2+ homeostasis and brain network excitability

Cited by 8 publications

References 15 publications

Dampened Slow Oscillation Connectivity Anticipates Amyloid Deposition in the PS2APP Mouse Model of Alzheimer’s Disease

Dampened Slow Oscillation Connectivity Anticipates Amyloid Deposition in the PS2APP Mouse Model of Alzheimer’s Disease

Intracellular Calcium Dysregulation by the Alzheimer’s Disease-Linked Protein Presenilin 2

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

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