The Amino-Terminal Region of Amyloid Precursor Protein Is Responsible for Neurite Outgrowth in Rat Neocortical Explant Culture

Ohsawa, Ikuroh; Takamura, Chizuko; Kohsaka, Shinichi

doi:10.1006/bbrc.1997.6903

Cited by 60 publications

(48 citation statements)

References 24 publications

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“…Development 135 (6) ( Ohsawa et al, 1999), synaptogenesis (Morimoto et al, 1998) and neurite growth (Small et al, 1994;Ohsawa et al, 1997), consistent with the possibility that interactions with contactins could be involved in these biological processes. APP also associated in our co-precipitation experiments with NgCAM.…”

Section: Research Articlementioning

confidence: 76%

Interaction of amyloid precursor protein with contactins and NgCAM in the retinotectal system

et al. 2008

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The amyloid precursor protein (APP) plays a central role in Alzheimer's disease, but its actions in normal development are not well understood. Here, a tagged APP ectodomain was used to identify extracellular binding partners in developing chick brain. Prominent binding sites were seen in the olfactory bulb and on retinal axons growing into the optic tectum. Co-precipitation from these tissues and tandem mass spectrometry led to the identification of two associated proteins: contactin 4 and NgCAM. In vitro binding studies revealed direct interactions among multiple members of the APP and contactin protein families. Levels of the APP processing fragment, CTF␣, were modulated by both contactin 4 and NgCAM. In the developing retinotectal system, APP, contactin 4 and NgCAM are expressed in the retina and tectum in suitable locations to interact. Functional assays revealed regulatory effects of both APP and contactin 4 on NgCAM-dependent growth of cultured retinal axons, demonstrating specific functional interactions among these proteins. These studies identify novel binding and functional interactions among proteins of the APP, contactin and L1CAM families, with general implications for mechanisms of APP action in neural development and disease.

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Section: Research Articlementioning

confidence: 76%

Interaction of amyloid precursor protein with contactins and NgCAM in the retinotectal system

et al. 2008

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“…It has been shown that APP can function as a cell adhesion molecule (43)(44)(45) because the membrane-bound form has structural similarities to other known adhesion molecules (46). Further, APP s also has been reported to have trophic and neuroprotective properties both in vitro (47)(48)(49) and in vivo (6). These findings may be relevant to a possible function of this protein in memory consolidation by stabilizing contacts between cells, and particularly by consolidating or strengthening certain synapses involved in the memory trace.…”

Section: Discussionmentioning

confidence: 98%

Memory-enhancing effects of secreted forms of the β-amyloid precursor protein in normal and amnestic mice

Méziane¹,

Dodart²,

Mathis³

et al. 1998

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

324

216

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When administered intracerebroventricularly to mice performing various learning tasks involving either short-term or long-term memory, secreted forms of the ␤-amyloid precursor protein (APP s 751 and APP s 695 ) have potent memory-enhancing effects and block learning deficits induced by scopolamine. The memory-enhancing effects of APP s were observed over a wide range of extremely low doses (0.05-5,000 pg intracerebroventricularly), blocked by anti-APP s antisera, and observed when APP s was administered either after the first training session in a visual discrimination or a lever-press learning task or before the acquisition trial in an object recognition task. APP s had no effect on motor performance or exploratory activity. APP s 695 and APP s 751were equally effective in the object recognition task, suggesting that the memory-enhancing effect of APP s does not require the Kunitz protease inhibitor domain. These data suggest an important role for APP s s on memory processes.Alzheimer's disease (AD) is the most common cause of progressive cognitive decline and dementia in aged humans. The deposition of the ␤-amyloid peptide(s) (A␤) in extracellular neuritic plaques of AD patients is an early and invariant feature of this neurodegenerative disorder (1). A␤ is derived from a large membrane-spanning ␤-amyloid precursor protein (APP), encoded by a single gene located on chromosome 21. Alternative splicing of this gene in humans leads to three major isoforms, either lacking (APP 695 ) or containing (APP 751 and APP 770 ) a Kunitz protease inhibitor domain. APP 695 is selectively expressed in the brain, whereas APP 751 and APP 770 also are abundantly expressed in peripheral tissues. Proteolytic processing of APPs at the N-and C-termini by ␤-and ␥-secretases leads to the production of A␤ (2). An alternative cleavage by ␣-secretase(s) within the A␤ domain of APPs generates secreted N-terminal products, the secreted APPs (APP s s) (2). The normal physiological functions of APPs and secreted derivatives are still poorly understood. However, neurotrophic as well as neuroprotective actions have been reported for both APP s 751 and APP s 695 (3-6). Recent behavioral studies have shown that intracerebroventricular (i.c.v.) administration of anti-APPs antisera results in memory impairment in rats performing a passive avoidance task (7,8). Further, the induction of long-term potentiation in hippocampal slices is associated with increased APP s synthesis and secretion (9). These data suggest that APP s s may be involved in learning and memory processes. In the present study, we investigated whether APP s 751 and APP s 695 have memoryenhancing actions when directly administered to mice performing various learning tasks and to mice rendered amnestic by administering the anticholinergic drug scopolamine.

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“…We hypothesize that the presence of APPs-␣/␤ may actually exacerbate certain APP lossof-function phenotypes. This hypothesis is based on the effects of APP in neurite outgrowth assays: both the deletion of APP in mixed neuronal and glial cultures and the addition of APPs-␣ to cultured neurons independently increased neurite outgrowth in vitro (Araki et al, 1991;Milward et al, 1992;Ohsawa et al, 1995Ohsawa et al, , 1997Perez et al, 1997;Wallace et al, 1997). Studies from our lab suggest that this activity of APPs in the neurite outgrowth assay may result from its competition with cell surface APP for interaction with binding partners (T. L. Young-Pearse and D. J. Selkoe, unpublished observation).…”

Section: App Extracellular and Intracellular Domains Are Both Necessamentioning

confidence: 99%

A Critical Function for β-Amyloid Precursor Protein in Neuronal Migration Revealed byIn UteroRNA Interference

Young‐Pearse¹,

Bai²,

Chang³

et al. 2007

J. Neurosci.

322

306

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Physiological processing of the ␤-amyloid precursor protein (APP) generates amyloid ␤-protein, which can assemble into oligomers that mediate synaptic failure in Alzheimer's disease. Two decades of research have led to human trials of compounds that chronically target this processing, and yet the normal function of APP in vivo remains unclear. We used the method of in utero electroporation of shRNA constructs into the developing cortex to acutely knock down APP in rodents. This approach revealed that neuronal precursor cells in embryonic cortex require APP to migrate correctly into the nascent cortical plate. cDNAs encoding human APP or its homologues, amyloid precursor-like protein 1 (APLP1) or APLP2, fully rescued the shRNA-mediated migration defect. Analysis of an array of mutations and deletions in APP revealed that both the extracellular and cytoplasmic domains of APP are required for efficient rescue. Whereas knock-down of APP inhibited cortical plate entry, overexpression of APP caused accelerated migration of cells past the cortical plate boundary, confirming that normal APP levels are required for correct neuronal migration. In addition, we found that Disabled-1 (Dab1), an adaptor protein with a well established role in cortical cell migration, acts downstream of APP for this function in cortical plate entry. We conclude that full-length APP functions as an important factor for proper migration of neuronal precursors into the cortical plate during the development of the mammalian brain.

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The Amino-Terminal Region of Amyloid Precursor Protein Is Responsible for Neurite Outgrowth in Rat Neocortical Explant Culture

Cited by 60 publications

References 24 publications

Interaction of amyloid precursor protein with contactins and NgCAM in the retinotectal system

Interaction of amyloid precursor protein with contactins and NgCAM in the retinotectal system

Memory-enhancing effects of secreted forms of the β-amyloid precursor protein in normal and amnestic mice

A Critical Function for β-Amyloid Precursor Protein in Neuronal Migration Revealed byIn UteroRNA Interference

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