The role of lipoprotein receptors on the physiological function of APP

Wagner, Timo; Pietrzik, Claus U.

doi:10.1007/s00221-011-2876-8

Cited by 27 publications

(22 citation statements)

References 93 publications

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“…A decreased aggregation propensity, analogical to the herein reported effect of murine APP co-expression, not only restricts accumulation and aggregation but makes Aβ better available for degradation [3] and promotes its elimination. The extent of aggregation interference, peripheral and central degradation and the efflux across the blood-brain barrier by LRP1 [17, 38] and different ABC-transporters [20, 26] might, therefore, been estimated inaccurately. The co-expression of murine APP may, thus, impede transferability of results to the human system.…”

Section: Discussionmentioning

confidence: 99%

Expression of endogenous mouse APP modulates β-amyloid deposition in hAPP-transgenic mice

Steffen

Krohn

Schwitlick

et al. 2017

acta neuropathol commun

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Amyloid-β (Aβ) deposition is one of the hallmarks of the amyloid hypothesis in Alzheimer’s disease (AD). Mouse models using APP-transgene overexpression to generate amyloid plaques have shown to model only certain parts of the disease. The extent to which the data from mice can be transferred to man remains controversial. Several studies have shown convincing treatment results in reducing Aβ and enhancing cognition in mice but failed totally in human. One model-dependent factor has so far been almost completely neglected: the endogenous expression of mouse APP and its effects on the transgenic models and the readout for therapeutic approaches.Here, we report that hAPP-transgenic models of amyloidosis devoid of endogenous mouse APP expression (mAPP-knockout / mAPPko) show increased amounts and higher speed of Aβ deposition than controls with mAPP. The number of senile plaques and the level of aggregated hAβ were elevated in mAPPko mice, while the deposition in cortical blood vessels was delayed, indicating an alteration in the general aggregation propensity of hAβ together with endogenous mAβ. Furthermore, the cellular response to Aβ deposition was modulated: mAPPko mice developed a pronounced and age-dependent astrogliosis, while microglial association to amyloid plaques was diminished. The expression of human and murine aggregation-prone proteins with differing amino acid sequences within the same mouse model might not only alter the extent of deposition but also modulate the route of pathogenesis, and thus, decisively influence the study outcome, especially in translational research.

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Section: Discussionmentioning

confidence: 99%

Expression of endogenous mouse APP modulates β-amyloid deposition in hAPP-transgenic mice

Steffen

Krohn

Schwitlick

et al. 2017

acta neuropathol commun

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“…Recently, the Fe65-mediated interaction between two further receptors of the LDL receptor gene family and APP, namely megalin (LRP2) and the very-low density lipoprotein receptor, has been reported (Alvira-Botero et al, 2010; Dumanis et al, 2012). For more in-depth discussions of the implication of LRPs for AD progression, the reader is referred to excellent reviews on this topic (Bu, 2009;Herz, 2009;Wagner and Pietrzik, 2012). …”

Section: Endocytic Receptors Modulate the Internalization Of Appmentioning

confidence: 99%

“…All known members of the VPS10-domain receptor family are shown to include the yeast receptor VPS10 and the vertebrate proteins sortilin, SORLA, as well as SORCS1, SORCS2 and SORCS3. For LRPs, the only receptors depicted are those that have been shown to interact with APP (reviewed in Bu, 2009;Wagner and Pietrzik, 2012). (B) Newly synthesized pro-SORLA is activated in the Golgi by convertase cleavage.…”

Section: Lrp1mentioning

confidence: 99%

Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease

Willnow

Andersen

2013

Journal of Cell Science

100

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SummaryExcessive proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid b peptides (Ab) by secretases in the brain is a molecular cause of Alzheimer disease (AD). According to current concepts, the complex route whereby APP moves between the secretory compartment, the cell surface and endosomes to encounter the various secretases determines its processing fate. However, the molecular mechanisms that control the intracellular trafficking of APP in neurons and their contribution to AD remain poorly understood. Here, we describe the functional elucidation of a new sorting receptor SORLA that emerges as a central regulator of trafficking and processing of APP. SORLA interacts with distinct sets of cytosolic adaptors for anterograde and retrograde movement of APP between the trans-Golgi network and early endosomes, thereby restricting delivery of the precursor to endocytic compartments that favor amyloidogenic breakdown. Defects in SORLA and its interacting adaptors result in transport defects and enhanced amyloidogenic processing of APP, and represent important risk factors for AD in patients. As discussed here, these findings uncovered a unique regulatory pathway for the control of neuronal protein transport, and provide clues as to why defects in this pathway cause neurodegenerative disease.

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“…22 Some studies have shown that ε4 allele frequency is significantly increased among patients with AD and that this association might be related to a cognitive decline and a faster disease progression, contributing to the reduction of the median age for AD onset. 9,14,23 FXTAS is a late-onset neurodegenerative disorder molecularly characterized by increased levels of abnormal (expanded CGG repeat) FMR1 mRNA and slightly reduced fragile X mental retardation protein levels.…”

Section: Discussionmentioning

confidence: 99%

High apolipoprotein E4 allele frequency in FXTAS patients

Silva¹,

Rodríguez‐Revenga²,

Madrigal³

et al. 2013

Genetics in Medicine

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Original research articleFragile X-associated tremor/ataxia syndrome (FXTAS, OMIM no. 300623) is a late-onset neuropsychiatric degenerative disorder that occurs in FMR1 premutation carriers . Clinical symptoms, which appear in patients in their 50s or later, include action tremor, progressive cerebellar ataxia, peripheral neuropathy, autonomic dysfunction, cognitive decline, and dementia. [1][2][3][4] Magnetic resonance imaging in patients with FXTAS demonstrates mild to moderate cerebellar and brain atrophy, as well as white matter hyperintensities. In addition, hyperintensities in the middle cerebellar peduncles on T2 have been described as a characteristic finding in patients with FXTAS and therefore constitute a major diagnostic feature of the disorder.3,5 It has been estimated that at least one-third of all FMR1 premutation carriers will develop an FXTAS syndrome, although there is significant variability in the progression of neurological dysfunction. 2,6,7 Apolipoprotein E (ApoE) is a lipoprotein that transports cholesterol and other lipids and lipid-soluble molecules into the central nervous system. [8][9][10][11] ApoE also modulates the inflammatory response to cellular damage in the brain.12 The human ApoE gene shows polymorphic variation, and three alleles, designated as ApoE ε2, ε3, and ε4, are common in the general population. 13 Variant distribution of these alleles has been shown to be associated with a number of age-related diseases including atherosclerosis, cardiovascular disease, and neurodegenerative disorders.14-16 Although the pathogenic mechanism involving ApoE in these diseases is still unclear, it has been demonstrated that the ApoE ε4 allele is a well-established genetic risk factor for neurodegenerative disorders including Alzheimer disease (AD), Parkinson disease, and other disorders in which dementia is present. [17][18][19] On the basis of this observation, we have evaluated the ApoE genotypes and allelic distribution among a FMR1 premutation carrier cohort presenting with FXTAS. These data might contribute to uncover a new genetic risk factor for FXTAS and might be useful to identify new genes involved in the disease onset and progression. METHODS SubjectsA total of 44 unrelated FMR1 premutation carriers (22 presenting with FXTAS symptoms and 22 without FXTAS clinical symptoms) were included. Samples from subjects belong to the Hospital Clinic of Barcelona and were molecularly diagnosed in the genetics laboratory of the same hospital. All participants were enrolled from families with members known to be affected with fragile X syndrome, and all of them are of Caucasian ethnicity. A classification on the basis of the gender and the age of the participants is summarized in Table 1. Although clinical data is scarce for some of the patients and we did not diagnose dementia in all of them, none of the cases included in the study had a diagnosis of AD. Overall, FXTAS encompasses patients who meet criteria in any of the three categories of involvement: definite, probable, and possible.3 ...

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The role of lipoprotein receptors on the physiological function of APP

Cited by 27 publications

References 93 publications

Expression of endogenous mouse APP modulates β-amyloid deposition in hAPP-transgenic mice

Expression of endogenous mouse APP modulates β-amyloid deposition in hAPP-transgenic mice

Sorting receptor SORLA – a trafficking path to avoid Alzheimer disease

High apolipoprotein E4 allele frequency in FXTAS patients

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