Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor.

Roch, Jean‐Marc; Masliah, Eliezer; Roch‐Levecq, Anne‐Catherine; Sundsmo, Mary; Otero, Deborah A. C.; Veinbergs, Isaac; Saitoh, Tsuano

doi:10.1073/pnas.91.16.7450

Cited by 229 publications

(126 citation statements)

References 17 publications

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…Indeed, studies on neuronal or non-neuronal cultures have demonstrated that APP s can promote cell growth. In this regard, Roch et al (25) have shown that a peptide containing the neurotrophic domain of APP increases the number of synapses in the cortex of rats during learning in the water maze. Moreover, Huber et al (50) recently have reported that the number of synapses and the level of endogenous APP at synapses in the cerebral cortex are increased in rats bred in an enriched environment, compared with rats bred in standard conditions, again suggesting a role for APP in the formation of new synapses during learning.…”

Section: Discussionmentioning

confidence: 99%

“…However, nonspatial͞item recognition memory depends on cortical structures (e.g., visual association areas, perirhinal, entorhinal, and the frontal cortices) rather than the hippocampus per se (24). A peptide derived from APP was shown to increase the number of presynaptic terminals in the frontoparietal cortex of rats at doses improving memory retention in a water maze (25).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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.

326

216

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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.

326

216

View full text Add to dashboard Cite

show abstract

“…These observations provide a mechanistic link between hAPP and excitoprotective effects observed in different in vivo models (5,(25)(26)(27). Our findings also suggest that alterations of hAPP levels or functions by genetic or environmental processes could impair astroglial glutamate/aspartate uptake and thereby result in excitotoxicity and disturbed neurotransmission.…”

Section: Fig 5 Effect Of Recombinant S-happ695 and S-happ751 Onmentioning

confidence: 99%

“…The levels of neuronal hAPP expression directed by the NSE promoter resulted in only moderate elevations of total APP expression above levels found in nontransgenic controls and, hence, were substantially lower than those found in hAPP models that develop Alzheimer's disease-type neuropathology (8,(22)(23)(24). NSE-driven neuronal overexpression of hAPP in transgenic mice or intracerebroventricular infusion of hAPP fragments in nontransgenic rodents increased the number of presynaptic terminals in the neocortex and protected neurons against ischemia and excitotoxins (5,22,(25)(26)(27), suggesting that APP may fulfill important neurotrophic and neuroprotective functions in vivo. In vitro studies suggest that s-APP may prevent excitotoxicity by stabilizing intraneuronal calcium levels (4).…”

mentioning

confidence: 99%

Amyloid Protein Precursor Stimulates Excitatory Amino Acid Transport

Masliah¹,

Raber²,

Alford³

et al. 1998

Journal of Biological Chemistry

View full text Add to dashboard Cite

Excitatory neurotransmitters such as glutamate are required for the normal functioning of the central nervous system but can trigger excitotoxic neuronal injury if allowed to accumulate to abnormally high levels. Their extracellular levels are controlled primarily by transmitter uptake into astrocytes. Here, we demonstrate that the amyloid protein precursor may participate in the regulation of this important process. The amyloid protein precursor has been well conserved through evolution, and a number of studies indicate that it may function as an endogenous excitoprotectant. However, the mechanisms underlying this neuroprotective capacity remain largely unknown. At moderate levels of expression, human amyloid protein precursors increased glutamate/aspartate uptake in brains of transgenic mice, with the 751-amino acid isoform showing greater potency than the 695-amino acid isoform. Cerebral glutamate/aspartate transporter protein levels were higher in transgenic mice than in non-transgenic controls, whereas transporter mRNA levels were unchanged. Amyloid protein precursor-dependent stimulation of aspartate uptake by cultured primary astrocytes was associated with increases in protein kinase A and C activity and could be blocked by inhibitors of these kinases. The stimulation of astroglial excitatory amino acid transport by amyloid protein precursors could protect the brain against excitotoxicity and may play an important role in neurotransmission.

show abstract

“…A 17 amino acid peptide fragment immediately C-terminal to the KPI domain is probably responsible for the memory enhancing properties of APP and may lead to an increase in the number of presynaptic terminals [138].…”

Section: In Vivo Studies: Appmentioning

confidence: 99%

The Functions of the Amyloid Precursor Protein Gene and Its Derivative Peptides: II Experimental Evidence and Clinical Studies

Panegyres¹,

Atkins²

2011

View full text Add to dashboard Cite

show abstract

Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor.

Abstract: NeurobiologyIncrease of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid ,t/A4 protein precursor (

Cited by 229 publications

References 17 publications

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

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

Amyloid Protein Precursor Stimulates Excitatory Amino Acid Transport

The Functions of the Amyloid Precursor Protein Gene and Its Derivative Peptides: II Experimental Evidence and Clinical Studies

Contact Info

Product

Resources

About