Genetic Restoration of Plasma ApoE Improves Cognition and Partially Restores Synaptic Defects in ApoE-Deficient Mice

Lane-Donovan, Courtney; Wong, Wen Mai; Durakoglugil, Murat S.; Wasser, Catherine R.; Jiang, Shan; Xian, Xunde; Herz, Joachim

doi:10.1523/jneurosci.1054-16.2016

Cited by 86 publications

(76 citation statements)

References 54 publications

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“…This result contrasts previous results showing that the APP intracellular domain can drive ApoE gene transcription and may highlight differences between AD models and the complexity of ApoE biology (Liu et al, 2007). A variety of ApoE receptors localize to the post synaptic membrane and include Lrp1, Apoer2, and Vldlr which interact with several synaptic scaffolds and glutamate receptors (Lane-Donovan et al, 2016).…”

Section: Toxic Aβ Levels Drive Non-linear Proteome Remodelingcontrasting

confidence: 88%

Amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimer’s disease like pathology

Savas¹,

Wang²,

DeNardo

et al. 2017

Preprint

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SummaryAmyloid beta (Aβ) peptides impair multiple cellular pathways in the brain and play a causative role in Alzheimer's disease (AD) pathology, but how the brain proteome is remodeled during this process is unknown. To identify new protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at pre-and post-symptomatic ages. Our analysis revealed a robust and consistent increase in Apolipoprotein E (ApoE) levels in nearly all transgenic brain regions with increased Aβ levels. Taken together with prior findings on ApoE driving Aβ accumulation, this analysis points to a pathological dysregulation of the ApoE-Aβ axis. We also found dysregulation of protein networks involved in excitatory synaptic transmission consistent with AD pathophysiology. Targeted analysis of the AMPA receptor complex revealed a specific loss of TARPγ-2, a key AMPA receptor trafficking protein. Expression of TARPγ-2 in vivo in hAPP transgenic mice led to a restoration of AMPA currents. This database of proteome alterations represents a unique resource for the identification of protein alterations responsible for AD. Highlights• Proteomic analysis of mouse brains with AD-like pathology reveals stark remodeling• Proteomic evidence points to a dysregulation of ApoE levels associated with Aβ clearance rather than production• Co-expression analysis found distinctly impaired synapse and mitochondria modules• In-depth analyses of AMPAR complex points to loss of TARPγ-2, which may compromise synapses in AD eTOC BlurbProteome-wide profiling of brain tissue from three mouse models of AD-like pathology reveals Aβ, brain region, and age dependent alterations of protein levels. This resource provides a new global protein expression atlas for the Alzheimer's disease research community. peer-reviewed)

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Section: Toxic Aβ Levels Drive Non-linear Proteome Remodelingcontrasting

confidence: 88%

Amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimer’s disease like pathology

Savas¹,

Wang²,

DeNardo

et al. 2017

Preprint

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“…ApoE is mainly produced by hepatocytes and macrophages in the peripheral tissues, whereas in the CNS, apoE is highly expressed by astrocytes (Xu et al, 2006). The blood-brain barrier limits the transport of apoE into and out of the brain such that peripheral and cerebral apoE molecules are in separate pools (Lane-Donovan et al, 2016). The plasma apoE is desialylated and preferentially associated with very low-density lipoprotein particles, whereas the apoE in the CNS is found in high-density lipoprotein (HDL)-like particles (Kim et al, 2009b).…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes

Zhao

Liu

Ingelgom

et al. 2017

Neuron

219

203

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SUMMARY Diabetes and impaired brain insulin signaling are linked to the pathogenesis of Alzheimer’s disease (AD). The association between diabetes and AD-associated amyloid pathology is stronger among carriers of the apolipoprotein E (APOE) ε4 gene allele, the strongest genetic risk factor for late-onset AD. Here we report that apoE4 impairs neuronal insulin signaling in human apoE-targeted replacement (TR) mice in an age-dependent manner. High fat diet (HFD) accelerates these effects in apoE4-TR mice at middle age. In primary neurons, apoE4 interacts with insulin receptor and impairs its trafficking by trapping it in the endosomes, leading to impaired insulin signaling and insulin-stimulated mitochondrial respiration and glycolysis. In aging brains, the increased apoE4 aggregation and compromised endosomal function further exacerbate the inhibitory effects of apoE4 on insulin signaling and related functions. Together, our study provides novel mechanistic insights into the pathogenic mechanisms of apoE4 and insulin resistance in AD.

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“…Previous studies have shown that ApoE knockout mice have cognitive deficits that are more pronounced in females and are exacerbated by age in association with BBB dysfunction (71)(72)(73). Based on the approach of targeted replacement with either full-length or truncated forms of human apoE in ApoE -/-mice (19,71,73), in future it would be interesting to use a similar approach to test for the potential protective effect of the apoE 25 kDa fragment on synaptic and cognitive dysfunctions in vivo.…”

Section: Discussionmentioning

confidence: 99%

The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis

Muñoz

Liu

Ruberu

et al. 2018

Journal of Biological Chemistry

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Apolipoprotein-E (apoE) is a glycoprotein highly expressed in the brain, where it appears to play a role in lipid transport, b-amyloid clearance, and neuronal signaling. ApoE proteolytic fragments are also present in the brain, but the enzymes responsible for apoE fragmentation are unknown, and the biological activity of specific apoE fragments remains to be determined. Here we utilised SK-N-SH neuroblastoma cells differentiated into neurons with all-trans retinoic acid (ATRA) to study extracellular apoE proteolysis. ApoE fragments were detectable in culture supernatants after 3 days, and their levels were increased for up to 9 days in the presence of ATRA. The concentration of apoE fragments was positively correlated with levels of the neuronal maturation markers (PSD95 and SMI32). The most abundant apoE fragments were 25 kDa and 28 kDa N-terminal fragments that both contained sialylated glycosylation and bound to heparin. We detected apoE fragments only in the extracellular milieu and not in cell lysates, suggesting that an extracellular protease contributes to apoE fragmentation.Of note, siRNA-mediated knockdown of high-temperature requirement serine peptidase A1 (HtrA1) and a specific HtrA1 inhibitor reduced apoE 25 kDa fragment formation by 41% and 86%, respectively. Recombinant 25-kDa fragment apoE and full-length apoE both stimulated neuritogenesis in vitro, increasing neuroblastoma neurite growth by more than 2-fold over a 6-day period. This study provides a cellular model for assessing apoE proteolysis, indicates that HtrA1 regulates apoE 25-kDa fragment formation under physiological conditions, and reveals a new neurotrophic function for the apoE 25-kDa fragment. ________________________________________

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Genetic Restoration of Plasma ApoE Improves Cognition and Partially Restores Synaptic Defects in ApoE-Deficient Mice

Cited by 86 publications

References 54 publications

Amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimer’s disease like pathology

Amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimer’s disease like pathology

Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes

The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis

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