Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

Sepulveda‐Falla, Diego; Barrera-Ocampo, Álvaro; Hagel, Christian; Korwitz, Anne; Vinueza-Veloz, María Fernanda; Zhou, Kai; Schonewille, Martijn; Zhou, Haibo; Velázquez‐Pérez, Luis; Labrada, Roberto Rodríguez; Villegas, Andrés; Ferrer, Isidro; Lopera, Francisco; Länger, Thomas; Zeeuw, Chris I. De; Glatzel, Markus

doi:10.1172/jci66407

Cited by 111 publications

(91 citation statements)

References 74 publications

(73 reference statements)

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“…Our conclusions are consistent with the observation that neuronal excitability and synaptic transmission are affected in these animals (35)(36)(37)(38). Remarkably, in the FAD patients associated with PS1, cerebellar dysfunction, including ataxia, Purkinje cell simple spike activity, and mitochondrial transport, occurs before the appearance of Aβ deposition (39).…”

Section: Discussionsupporting

confidence: 92%

Selective filtering defect at the axon initial segment in Alzheimer’s disease mouse models

Sun

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Axon pathology has been widely reported in Alzheimer’s disease (AD) patients and AD mouse models. Herein we report that increased miR-342–5p down-regulates the expression of ankyrin G (AnkG), a protein known to play a critical role in establishing selective filtering machinery at the axon initial segment (AIS). Diminished AnkG expression leads to defective AIS filtering in cultured hippocampal neurons from AD mouse models, as monitored by selective exclusion of large macromolecules from the axons. Furthermore, AnkG-deficiency impairs AIS localization of Nav 1.6 channels and confines NR2B to the somatodendritic compartments. The expression of exogenous AnkG improved the cognitive performance of 12-mo-old APP/PS1 mice; thus, our data suggest that AnkG and impairment of AIS filtering may play important roles in AD pathology.

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Section: Discussionsupporting

confidence: 92%

Selective filtering defect at the axon initial segment in Alzheimer’s disease mouse models

Sun

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…In all three investigated brain regions, rpAD patients displayed significantly higher levels of TMEM119 immunopositivity than sCJD patients. These findings are consistent with recent clinical and neuroimaging studies in humans, showing cerebellar involvement also in AD …”

Section: Discussionsupporting

confidence: 93%

Distinct microglia profile in Creutzfeldt–Jakob disease and Alzheimer's disease is independent of disease kinetics

et al. 2018

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Activated microglia represent a common pathological feature of neurodegenerative diseases. Sporadic Creutzfeldt–Jakob disease (sCJD) patients show more pronounced microglial activation than Alzheimer's disease (AD) patients. Whether these differences are due to differences in disease kinetics or represent disease‐specific changes is unknown. We investigated microglial phenotypes in brains of rapidly progressive AD (rpAD) and sCJD patients matched for clinical presentation, including disease duration. We immunostained the frontal cortex, basal ganglia and cerebellum in 16 patients with rpAD and sCJD using antibodies against markers of microglia and recruited monocytes (ionized calcium‐binding adaptor molecule 1, human leukocyte antigen DPQR, Cluster of Differentiation 68), an antibody unique to brain‐resident microglia (transmembrane protein 119 (TMEM119)), in addition to antibodies against a marker of astrocytes (glial fibrillary acidic protein), amyloid‐β (Aβ) and pathological prion protein. rpAD patients showed a distinct microglial phenotype with a high abundance of TMEM119‐positive microglia in all investigated regions. Presence of Aβ deposits seen in a sCJD patient with concomitant deposition of Aβ led to increase of TMEM119‐positive microglia. Our data suggest that in rpAD, activation of brain‐resident microglia significantly contributes to microgliosis, whereas in sCJD the TMEM119 signature of resident microglial cells is barely detectable. This is irrespective of disease duration and may indicate disease‐specific microglial reaction.

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“…Also, neuroimaging techniques have shown extensive plaque formation in people with no cognitive impairment (Nordberg 2008;Villemagne et al 2008). Furthermore, mitochondria dysfunction is highly reported in AD models and patients and may occur prior to the formation of amyloid plaques (Swerdlow et al 2010;Cali et al 2012;Leuner et al 2012;Schon and Area-Gomez 2013;Sepulveda-Falla et al 2014). While these previous studies suggest that amyloid Figure 7 sel-12 mutants have mitochondrial functional defects.…”

Section: Discussionmentioning

confidence: 99%

A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans

Sarasija¹,

Norman

2015

Genetics

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Mutations in the presenilin (PSEN) encoding genes (PSEN1 and PSEN2) occur in most early onset familial Alzheimer's Disease. Despite the identification of the involvement of PSEN in Alzheimer's Disease (AD) 20 years ago, the underlying role of PSEN in AD is not fully understood. To gain insight into the biological function of PSEN, we investigated the role of the PSEN homolog SEL-12 in Caenorhabditis elegans. Using genetic, cell biological, and pharmacological approaches, we demonstrate that mutations in sel-12 result in defects in calcium homeostasis, leading to mitochondrial dysfunction. Moreover, consistent with mammalian PSEN, we provide evidence that SEL-12 has a critical role in mediating endoplasmic reticulum (ER) calcium release. Furthermore, we found that in SEL-12-deficient animals, calcium transfer from the ER to the mitochondria leads to fragmentation of the mitochondria and mitochondrial dysfunction. Additionally, we show that the impact that SEL-12 has on mitochondrial function is independent of its role in Notch signaling, g-secretase proteolytic activity, and amyloid plaques. Our results reveal a critical role for PSEN in mediating mitochondrial function by regulating calcium transfer from the ER to the mitochondria.KEYWORDS Caenorhabditis elegans; calcium; endoplasmic reticulum; mitochondria; presenilin M ITOCHONDRIA are highly dynamic organelles that are responsible for a myriad of functions including ATP production, generation and metabolism of reactive oxygen species (ROS), and apoptosis (Detmer and Chan 2007). Thus cells, in particular muscle cells and neurons due to their highenergy demands, are extremely reliant on mitochondrial function. Mitochondria also play a critical role in calcium homeostasis by acting as a calcium buffer. Calcium, in turn, regulates mitochondrial morphology, activity, and movement. The relevance of mitochondria is highlighted by the fact that many neurodegenerative diseases, such as Parkinson's and Alzheimer's Disease (AD) are characterized by abnormal mitochondrial activity and morphology (Cali et al. 2012).Mutations in the genes encoding presenilins (PSENs), PSEN1 and PSEN2, are the most common cause of early onset familial Alzheimer's Disease (FAD). PSENs are 50-kDa multipass transmembrane proteins that reside predominantly on the endoplasmic reticulum (ER) (Bezprozvanny and Mattson 2008) and have been shown to be enriched in an ER subcompartment that is in contact with mitochondria (Area-Gomez et al. 2009). Although altered PSEN function has been known to have a role in AD for 20 years (Sherrington et al. 1995), the functional consequences of mutations in PSENs are controversial and not understood. The prevailing model for the pathogenesis of AD is the "amyloid hypothesis," which states that an increase in b amyloid (Ab) 42 peptide is the major cause of neuronal degradation in AD (Hardy and Selkoe 2002); support for this hypothesis stems from the accumulation of amyloid plaques in the brains of AD patients (Hardy 2006). In addition to the "amyloid hypot...

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Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

Cited by 111 publications

References 74 publications

Selective filtering defect at the axon initial segment in Alzheimer’s disease mouse models

Selective filtering defect at the axon initial segment in Alzheimer’s disease mouse models

Distinct microglia profile in Creutzfeldt–Jakob disease and Alzheimer's disease is independent of disease kinetics

A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans

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