Localization Of Amyloid Precursor Protein Research Articles

Real-time heterogeneity of supramolecular assembly of amyloid precursor protein is modulated by an endocytic risk factor PICALM.

Recently, the localization of amyloid precursor protein (APP) into reversible nanoscale supramolecular assembly or "nanodomains" has been highlighted as crucial towards understanding the onset of the molecular pathology of Alzheimer's disease (AD). Surface expression of APP is regulated by proteins interacting with it, controlling its retention and lateral trafficking on the synaptic membrane. Here, we evaluated the involvement of a key risk factor for AD, PICALM, as a critical regulator of nanoscale dynamics of APP. Although it was enriched in the postsynaptic density, PICALM was also localized to the presynaptic active zone and the endocytic zone. PICALM colocalized with APP and formed nanodomains with distinct morphological properties in different subsynaptic regions. Next, we evaluated if this localization to subsynaptic compartments was regulated by the C-terminal sequences of APP, namely, the "Y682ENPTY687" domain. Towards this, we found that deletion of C-terminal regions of APP with partial or complete deletion of Y682ENPTY687, namely, APP-Δ9 and APP-Δ14, affected the lateral diffusion and nanoscale segregation of APP. Lateral diffusion of APP mutant APP-Δ14 sequence mimicked that of a detrimental Swedish mutant of APP, namely, APP-SWE, while APP-Δ9 diffused similar to wild-type APP. Interestingly, elevated expression of PICALM differentially altered the lateral diffusion of the APP C-terminal deletion mutants. These observations confirm that the C-terminal sequence of APP regulates its lateral diffusion and the formation of reversible nanoscale domains. Thus, when combined with autosomal dominant mutations, it generates distinct molecular patterns leading to onset of Alzheimer's disease (AD).

The localization of amyloid precursor protein to ependymal cilia in vertebrates and its role in ciliogenesis and brain development in zebrafish

Amyloid precursor protein (APP) is expressed in many tissues in human, mice and in zebrafish. In zebrafish, there are two orthologues, Appa and Appb. Interestingly, some cellular processes associated with APP overlap with cilia-mediated functions. Whereas the localization of APP to primary cilia of in vitro-cultured cells has been reported, we addressed the presence of APP in motile and in non-motile sensory cilia and its potential implication for ciliogenesis using zebrafish, mouse, and human samples. We report that Appa and Appb are expressed by ciliated cells and become localized at the membrane of cilia in the olfactory epithelium, otic vesicle and in the brain ventricles of zebrafish embryos. App in ependymal cilia persisted in adult zebrafish and was also detected in mouse and human brain. Finally, we found morphologically abnormal ependymal cilia and smaller brain ventricles in appa−/−appb−/− mutant zebrafish. Our findings demonstrate an evolutionary conserved localisation of APP to cilia and suggest a role of App in ciliogenesis and cilia-related functions.

Soluble 4R0N Tau Abrogates Endocytic Vesicular Dynamics.

Aggregated tau is a hallmark neuropathological feature in numerous neurodegenerative disorders. Previous studies aiming to validate aggregated tau pathology as a pathogenic driver of neurodegeneration in correlation to characteristic behavioral phenotypes have had shortcomings. Although studies on soluble tau pathology have effectively addressed these shortcomings, the role of soluble tau in the molecular pathogenesis of neurodegeneration is not yet unequivocally established. In sporadic Alzheimer’s disease (AD), the relevance of soluble tau pathology in endolysosomal dysfunction and autophagic stress, some of the earliest disease manifestations, is unclear. In this study, we report that soluble 4R0N tau overexpression affects the expression levels of certain markers associated with the endolysosomal system and autophagy. Moreover, through live-cell imaging, we found that the vesicular dynamics of early endosomes were affected with respect to spatiotemporal parameters and vesicle maturation. Additionally, we observed the localization of amyloid precursor protein (APP) along the endocytic pathway and found that upon overexpression of soluble 4R0N tau, APP was preferentially localized to the endocytic compartments implicated in the amyloidogenic pathway. Overall, our observations indicate that soluble 4R0N tau abrogates the dynamics of the endolysosomal system, autophagy, and affects the trafficking of APP. Since the amyloidogenic processing of APP occurs during its progression through the endocytic pathway, our results suggest that the generation of amyloid-β (Aβ) might also be modulated.

Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing

SORL1/SORLA is a sorting receptor involved in retromer-related endosomal traffic and an Alzheimer's disease (AD) risk gene. Using CRISPR-Cas9, we deplete SORL1 in hiPSCs to ask if loss of SORL1 contributes to AD pathogenesis by endosome dysfunction. SORL1-deficient hiPSC neurons show early endosome enlargement, a hallmark cytopathology of AD. There is no effect of SORL1 depletion on endosome size in hiPSC microglia, suggesting a selective effect on neuronal endosomal trafficking. We validate defects in neuronal endosomal traffic by showing altered localization of amyloid precursor protein (APP) in early endosomes, a site of APP cleavage by the β-secretase (BACE). Inhibition of BACE does not rescue endosome enlargement in SORL1-deficient neurons, suggesting that this phenotype is independent of amyloidogenic APP processing. Our data, together with recent findings, underscore how sporadic AD pathways regulating endosomal trafficking and autosomal-dominant AD pathways regulating APP cleavage independently converge on the defining cytopathology of AD.

Y682G Mutation of Amyloid Precursor Protein Promotes Endo-Lysosomal Dysfunction by Disrupting APP–SorLA Interaction

The intracellular transport and localization of amyloid precursor protein (APP) are critical determinants of APP processing and β-amyloid peptide production, thus crucially important for the pathophysiology of Alzheimer’s disease (AD). Notably, the C-terminal Y682ENPTY687 domain of APP binds to specific adaptors controlling APP trafficking and sorting in neurons. Mutation on the Y682 residue to glycine (Y682G) leads to altered APP sorting in hippocampal neurons that favors its accumulation in intracellular compartments and the release of soluble APPα. Such alterations induce premature aging and learning and cognitive deficits in APP Y682G mutant mice (APPYG/YG). Here, we report that Y682G mutation affects formation of the APP complex with sortilin-related receptor (SorLA), resulting in endo-lysosomal dysfunctions and neuronal degeneration. Moreover, disruption of the APP/SorLA complex changes the trafficking pathway of SorLA, with its consequent increase in secretion outside neurons. Mutations in the SorLA gene are a prognostic factor in AD, and changes in SorLA levels in cerebrospinal fluid are predictive of AD in humans. These results might open new possibilities in comprehending the role played by SorLA in its interaction with APP and in the progression of neuronal degeneration. In addition, they further underline the crucial role played by Y682 residue in controlling APP trafficking in neurons.

Directed Conversion of Alzheimer's Disease Patient Skin Fibroblasts into Functional Neurons

Directed conversion of mature human cells, as from fibroblasts to neurons, is of potential clinical utility for neurological disease modeling as well as cell therapeutics. Here, we describe the efficient generation of human-induced neuronal (hiN) cells from adultskin fibroblasts of unaffected individuals and Alzheimer's patients, using virally transduced transcription regulators and extrinsic support factors. hiN cells from unaffected individuals display morphological, electrophysiological, and gene expression profiles that typify glutamatergic forebrain neurons and are competent to integrate functionally into the rodent CNS. hiN cells from familial Alzheimer disease (FAD) patients with presenilin-1 or -2 mutations exhibit altered processing and localization of amyloid precursor protein (APP) and increased production of Aβ, relative to the source patient fibroblasts or hiN cells from unaffected individuals. Together, our findings demonstrate directed conversion of human fibroblasts to a neuronal phenotype and reveal cell type-selective pathology in hiN cells derived from FAD patients.

Aberrant localization of amyloid precursor protein in X11 and X11L- deficient mice brain

Aberrant localization of amyloid precursor protein in X11 and X11L- deficient mice brain

Altered localization of amyloid precursor protein under endoplasmic reticulum stress

Recent reports have shown that the endoplasmic reticulum (ER) stress is relevant to the pathogenesis of Alzheimer disease. Following the amyloid cascade hypothesis, we therefore attempted to investigate the effects of ER stress on amyloid-β peptide (Aβ) generation. In this study, we found that ER stress altered the localization of amyloid precursor protein (APP) from late compartments to early compartments of the secretory pathway, and decreased the level of Aβ 40 and Aβ 42 release by β- and γ-cutting. Transient transfection with BiP/GRP78 also caused a shift of APP and a reduction in Aβ secretion. It was revealed that the ER stress response facilitated binding of BiP/GRP78 to APP, thereby causing it to be retained in the early compartments apart from a location suitable for the cleavages of Aβ. These findings suggest that induction of BiP/GRP78 during ER stress may be one of the regulatory mechanisms of Aβ generation.

233 Localization of amyloid precursor protein (app), c-jun and p53 expression in the brain neurons undergoing induced apoptosis

International Journal of Developmental NeuroscienceVolume 14, Issue S1 p. 107-107 Article 233 Localization of amyloid precursor protein (app), c-jun and p53 expression in the brain neurons undergoing induced apoptosis K.T. Maśliski, K.T. MaśliskiSearch for more papers by this authorD. Maślina, D. MaślinaSearch for more papers by this author K.T. Maśliski, K.T. MaśliskiSearch for more papers by this authorD. Maślina, D. MaślinaSearch for more papers by this author First published: July-August 1996 https://doi.org/10.1016/0736-5748(96)80422-9AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume14, IssueS111th Biennial Meeting of the International Society for Developmental NeuroscienceJuly-August 1996Pages 107-107 RelatedInformation

Immunocytochemical localization of amyloid precursor protein in rat brain.

The localization of amyloid precursor protein (APP) in rat brain was studied with a cytoplasmic domain-specific antibody. Light microscopic immunocytochemistry demonstrated that APP is present in most neurons, in some oligodendrocytes, and in a population of cells with diameters less than 10 microns that may be glial. Marked differences in immunoreactivity among neurons were observed, and the strongest immunoreactivity was contained in larger neurons. Neurons with scant cytoplasm, such as granule cells in the olfactory bulb, dentate gyrus, and cerebellum, were weakly immunoreactive. Differences in neuropil immunoreactivity were also observed; this type of staining was strongest in the caudatoputamen, lateral septum, medial habenula, nucleus reticularis of the dorsal thalamus, and the lateral portion of the ventroposterior nucleus. Neuropil immunostaining was weakest in layer IV of cortex and in areas containing granule cells. The fact that APP seems to be present in the vast majority of neurons suggests that this protein plays a role common to all neurons. The fact that there is a great difference in the steady-state amount of APP among different types of neurons suggests that APP may play a specific role in the function of certain classes of neurons.

Localization of amyloid precursor protein in selective postsynaptic densities of rat cortical neurons

One of the hallmarks of Alzheimer pathology is extracellular deposition of β-amyloid protein (BAP) which is derived from a larger glycoprotein called amyloid precursor protein (APP). Although APP has often been described as a surface membrane protein, such a localization has not previously been demonstrated at the light on electron microscopic level. We now report the results of immunoelectron microscopy using three specific antibodies against different synthetic fragments of APP. All three antibodies demonstrated a major localization to organelles such as the Golgi apparatus, endoplasmic reticulum and vesicular-like structures. A minor proportion of staining with all three was on selective postsynaptic membranes of asymmetrical synapses, whereas staining of presynaptic membranes was not observed. The morphological evidence suggests that one role of APP may be in association with the function of selective synapses.

Localization of amyloid precursor protein in GAP43-immunoreactive aberrant sprouting neurites in Alzheimer's disease

Previous in vitro studies have suggested that amygloid precursor protein (APP) could be involved in cell surface adhesion, neuritic growth and survival of hippocampal neurons. In the present study, involvement of APP in aberrant sprouting in Alzheimer's disease (AD) was studied by comparing immunolabeling patterns of anti-APP and anti-growth-associated protein 43 (anti-GAP43). Confocal laser imaging of frontal cortex sections double-immunolabeled for APP and GAP43 showed an increase, in AD, of presynaptic boutons immunostained with anti-GAP43 that contained anti-APP immunoreactivity. The neuritic plaques in AD cases presented intense anti-GAP43 immunoreactive abnormal neurites colocalized with anti-APP. Three-dimensional reconstruction of the plaques showed that anti-APP was colocalized with anti-GAP43 in 57.5% of the aberrant sprouting neurites. We conclude that co-expression of APP with GAP43 in the plaque might be involved in the aberrant sprouting response observed in AD.