Cystatin C-Cathepsin B Axis Regulates Amyloid Beta Levels and Associated Neuronal Deficits in an Animal Model of Alzheimer's Disease

Sun, Binggui; Zhou, Yungui; Halabisky, Brian; Lo, Iris; Cho, Seo-Hyun; Mueller-Steiner, Sarah; Devidze, Nino; Wang, Xin; Grubb, Anders; Gan, Li

doi:10.1016/j.neuron.2008.10.001

Cited by 202 publications

(160 citation statements)

References 57 publications

Supporting

Mentioning

145

Contrasting

Unclassified

Order By: Relevance

“…Among the enzymes sorted by CI-MPR is CatB, a cysteine protease that degrades peptides in the endosomal-lysosomal system but also in the extracellular space following secretion (22). Because CatB specifically degrades A␤ 42 (23)(24)(25), we reasoned that the SORLA-independent effect of PACS1 knockdown on A␤ 42 levels might work by impacting the CI-MPR-CatB system. This hypothesis was supported when we detected reduced levels of CI-MPR in cell lysates (Fig.…”

Section: Resultsmentioning

confidence: 99%

SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes

Burgert

Schmidt

Çağlayan

et al. 2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

c Sorting-related receptor with A-type repeats (SORLA) is a sorting receptor for the amyloid precursor protein (APP) that prevents breakdown of APP into A␤ peptides, a hallmark of Alzheimer's disease (AD). Several cytosolic adaptors have been shown to interact with the cytoplasmic domain of SORLA, thereby controlling intracellular routing of SORLA/APP complexes in cell lines. However, the relevance of adaptor-mediated sorting of SORLA for amyloidogenic processes in vivo remained unexplored. We focused on the interaction of SORLA with phosphofurin acidic cluster sorting protein 1 (PACS1), an adaptor that shuttles proteins between the trans-Golgi network (TGN) and endosomes. By studying PACS1 knockdown in neuronal cell lines and investigating transgenic mice expressing a PACS1-binding-defective mutant form of SORLA, we found that disruption of SORLA and PACS1 interaction results in the inability of SORLA/APP complexes to sort to the TGN in neurons and in increased APP processing in the brain. Loss of PACS1 also impairs the proper expression of the cation-independent mannose 6-phosphate receptor and its target cathepsin B, a protease that breaks down A␤. Thus, our data identified the importance of PACS1-dependent protein sorting for amyloidogenic-burden control via both SORLA-dependent and SORLA-independent mechanisms.

show abstract

Section: Resultsmentioning

confidence: 99%

SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes

Burgert

Schmidt

Çağlayan

et al. 2013

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…In this study, we aimed to validate a PRM-MS assay consisting of a panel of proteins presumed to be involved in processes regarding secretory vesicle functioning, synaptic functioning, and innate immunity [12][13][14][15][16][17][18][19][20][21]. Having performed a pilot study [29], in the present study, we investigated this panel in a larger and independent cohort that included subjects with MCI in addition to patients with AD dementia and control subjects.…”

Section: Discussionmentioning

confidence: 99%

“…The PRM panel consisted of neurosecretory protein VGF (VGF), chromogranin A (CHGA), and secretogranin 2 (SCG2), granins that are presumed to be involved in axonal or synaptic vesicle transport (the granins VGF, CHGA, and SCG2) [12]; cystatin C (CysC), a protease involved in Aβ degradation [13,14]; β 2 -microglobulin (β 2 M) and lysozyme C (LysC), proteins involved in the innate immune system [15,16]; and neurexins (NRXNs) NRXN-1, NRXN-2, and NRXN-3 as well as neuronal pentraxin 1 (NPTX1), neurofascin (NFASC), and neurocan core protein (NCANP), proteins involved in synapse formation and stabilization [17][18][19][20][21]. Several of these proteins, including VGF, CHGA, SCG2, CysC, and β 2 M, have been suggested in previous studies to be involved in AD pathology [12][13][14][22][23][24][25][26][27][28]. A pilot study that we performed after developing the PRM panel showed promising results, with lower levels for several proteins in patients with AD dementia compared with control subjects [29].…”

Section: Introductionmentioning

confidence: 99%

Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer’s disease

et al. 2018

View full text Add to dashboard Cite

Background: We investigated whether a panel of 12 potential novel biomarkers consisting of proteins involved in synapse functioning and immunity would be able to distinguish patients with Alzheimer's disease (AD) and patients with mild cognitive impairment (MCI) from control subjects. Methods: We included 40 control subjects, 40 subjects with MCI, and 40 subjects with AD from the Amsterdam Dementia Cohort who were matched for age and sex (age 65 ± 5 years, 19 [48%] women). The mean follow-up of patients with MCI was 3 years. Two or three tryptic peptides per protein were analyzed in cerebrospinal fluid using parallel reaction monitoring mass spectrometry. Corresponding stable isotope-labeled peptides were added and used as reference peptides. Multilevel generalized estimating equations (GEEs) with peptides clustered per subject and per protein (as within-subject variables) were used to assess differences between diagnostic groups. To assess differential effects of individual proteins, we included the diagnosis × protein interaction in the model. Separate GEE analyses were performed to assess differences between stable patients and patients with progressive MCI (MCI-AD).Results: There was a main effect for diagnosis (p < 0.01) and an interaction between diagnosis and protein (p < 0.01). Analysis stratified according to protein showed higher levels in patients with MCI for most proteins, especially in patients with MCI-AD. Chromogranin A, secretogranin II, neurexin 3, and neuropentraxin 1 showed the largest effect sizes; β values ranged from 0.53 to 0.78 for patients with MCI versus control subjects or patients with AD, and from 0.67 to 0.98 for patients with MCI-AD versus patients with stable MCI. In contrast, neurosecretory protein VGF was lower in patients with AD than in patients with MCI (ß = −0.93 [SE 0.22]) and control subjects (ß = 0.46 [SE 0.19]). Conclusions: Our results suggest that several proteins involved in vesicular transport and synaptic stability are elevated in patients with MCI, especially in patients with MCI progressing to AD dementia. This may reflect early events in the AD pathophysiological cascade. These proteins may be valuable as disease stage or prognostic markers in an early symptomatic stage of the disease.

show abstract

“…CysC is thus likely indirectly involved in A␤ regulation. Epidemiologically, a polymor- phism in the CysC gene (CST3) has been linked to enhanced risk for AD (66), and CysC modulates cerebral ␤-amyloidosis in A␤PP transgenic mice (71).…”

Section: Cystatin Cmentioning

confidence: 99%

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Luo

Wärmländer

Gräslund

et al. 2016

Journal of Biological Chemistry

125

108

View full text Add to dashboard Cite

Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-␤ (A␤) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between A␤ and other amyloid proteins.Alzheimer disease (AD) 3 is the most common form of elderly dementia. Its causes have not yet been clearly elucidated. The two classical AD lesions are depositions of intracellular neurofibrillary tau tangles and extracellular deposits of aggregated amyloid-␤ (A␤) peptides in amyloid plaques in the gray matter of the brain, mainly the hippocampus and neocortex. A␤ is a 36 -43-residue peptide cleaved from the amyloid-␤ protein precursor (A␤PP) by ␥-secretase and ␤-secretase enzymes.Some A␤PP and A␤ mutations increase A␤ production and deposition and/or extend the half-life of A␤ in the brain, but only a fraction (5%) of Alzheimer disease is familial AD (1). Several studies indicate that alterations of the pathologies of other amyloid proteins such as ␣-synuclein (2) and tau (3) are observed in familial AD.The amyloid cascade hypothesis suggests that deposition of A␤ aggregates in brain plays a vital role in AD development (4). The amyloid form of A␤ aggregates is generally defined by in vitro observations: originally by the so-called cross-␤ x-ray diffraction pattern or by observation of fibril structures in microscopy (transmission electron microscopy or atomic force microscopy) (5). Molecular probes recognizing the formation of certain ordered molecular structures include Congo red and thioflavin T, which change their optical properties when bound to amyloid material (5). The terms "on-pathway" and "off-pathway" intermediates are used to differentiate between self-aggregated A␤ species that lead to amyloid formation and those that do not. Missense mutations in the A␤PP, apoE, PS1, and PS2 genes can increase accumulation and toxicity of A␤ aggregates, and the "on-pathway" intermediate aggregates seem to be the most cell-damaging species (6). This provides strong support for the amyloid cascade hypothesis, which nevertheless remains disputed.Although two recent reviews (7, 8) respectively reject and support the amyloid cascade hypothesis, they both agree on one poin...

show abstract

Cystatin C-Cathepsin B Axis Regulates Amyloid Beta Levels and Associated Neuronal Deficits in an Animal Model of Alzheimer's Disease

Cited by 202 publications

References 57 publications

SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes

SORLA-Dependent and -Independent Functions for PACS1 in Control of Amyloidogenic Processes

Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer’s disease

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Contact Info

Product

Resources

About