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

Abstract

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.

Involvement of β-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity

“…We dissociated the enhanced memory and synaptic plasticity in TgAPP mice from sAPP␣, which has been reported to enhance memory and synaptic plasticity in rats (3,4). Our findings are consistent with recent studies showing that sAPP␣ infused into the lateral ventricles of rats does not enhance LTP or cognitive function (21,22).…”

“…Activity-related regulation of APP cleavage has been proposed at the ␣-and ␤-secretase sites (1,2), suggesting a physiological role of APP and APP cleavage in the brain. The activation of M1 and M3 muscarinic acetylcholine receptors stimulates ␣-secretase activity and releases secreted APP␣ (sAPP␣) (1), which has been reported to enhance synaptic plasticity and memory (3,4). Synaptic activity triggers the regulated cleavage of APP through another pathway, by way of ␤-site APP cleaving enzyme 1 (BACE1), followed by ␥-and -secretase, releasing amyloid-␤ protein (A␤) (2,5) and AICD.…”

The Novel Membrane Protein TMEM59 Modulates Complex Glycosylation, Cell Surface Expression, and Secretion of the Amyloid Precursor Protein

“…Reagents and Antibodies-The following antibodies were used: anti-HA HA.11 (Covance) and 12CA5 (Roche), anti-FLAG (Sigma), anti-GFP (Clontech), anti-␤-actin, (Sigma), anti-calnexin (Stressgene), horseradish peroxidase-coupled goat anti-mouse and anti-rabbit (Promega), Alexa 555/Alexa 488-coupled secondary anti-mouse (Molecular Probes), Alexa 555-coupled secondary anti-rat antibody (Molecular Probes), Alexa 488-coupled anti-rabbit secondary antibody (Molecular Probes), anti-giantin (Alexis) (31), 6E10 (against A␤ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] , Senetek Inc.), 6687 (against APP C terminus) (32), 22C11 (against APP ectodomain, provided by Konrad Beyreuther), 192wt (specific for the C terminus of APPs␤, provided by Dale Schenk), W02 (against amino acids 5-8 of A␤, provided by Konrad Beyreuther) (33), 3552 (against A␤ ) (34), (against N terminus of BACE1, Sigma), Nicastrin (N1660, Sigma), and the antibodies GM130, GS15, GS27, GS28, p230, Syntaxin 6, Vti1a, and Vti1b of the Golgi Sampler Kit, as well as the antibody against TGN38 (both BD Transduction Laboratories). Polyclonal TMEM59-antiserum 93 was generated against a synthetic peptide (H 2 N-309 -323-CONH 2 ) from the C terminus of TMEM59 (Eurogentec Seraing, Belgium), 3F4 (antimouse PrP) (35).…”

Mechanisms by which metals promote events connected to neurodegenerative diseases

“…The A␤PP is postulated to have neurotropic properties [58,68,72,96]. The role of the protein in protecting neurons is supported by studies that show that A␤PP is upregulated during stressful conditions.…”