α-Secretase-derived fragment of cellular prion, N1, protects against monomeric and oligomeric amyloid ß (Aß)-associated cell death.

In physiological conditions, both ß-amyloid precursor protein (ßAPP) and cellular prion (PrP(c)) undergo similar disintegrin-mediated α-secretase cleavage yielding N-terminal secreted products referred to as soluble amyloid precursor protein-α (sAPPα) and N1, respectively. We recently demonstrated that N1 displays neuroprotective properties by reducing p53-dependent cell death both in vitro and in vivo. In this study, we examined the potential of N1 as a neuroprotector against amyloid ß (Aß)-mediated toxicity. We first show that both recombinant sAPPα and N1, but not its inactive parent fragment N2, reduce staurosporine-stimulated caspase-3 activation and TUNEL-positive cell death by lowering p53 promoter transactivation and activity in human cells. We demonstrate that N1 also lowers toxicity, cell death, and p53 pathway exacerbation triggered by Swedish mutated ßAPP overexpression in human cells. We designed a CHO cell line overexpressing the London mutated ßAPP (APP(LDN)) that yields Aß oligomers. N1 protected primary cultured neurons against toxicity and cell death triggered by oligomer-enriched APP(LDN)-derived conditioned medium. Finally, we establish that N1 also protects neurons against oligomers extracted from Alzheimer disease-affected brain tissues. Overall, our data indicate that a cellular prion catabolite could interfere with Aß-associated toxicity and that its production could be seen as a cellular protective mechanism aimed at compensating for an sAPPα deficit taking place at the early asymptomatic phase of Alzheimer disease.

Evidence that the amyloid-ß protein precursor intracellular domain, AICD, derives from ß-secretase-generated C-terminal fragment.

One of the major pathological hallmarks of brains affected with Alzheimer's disease (AD) is the senile plaque, an extracellular deposit mainly composed of a set of highly insoluble peptides of various lengths (39-43 amino acids) referred to as amyloid-ß (Aß) peptides. Aß peptides are derived from combined proteolytic cleavages undergone on the amyloid-ß protein precursor (AßPP) by a set of enzymes called secretases. Several lines of anatomical and biological evidence suggest that Aß peptides would not account for all pathological stigmata and molecular dysfunctions taking place in AD. In amyloidogenic and non-amyloidogenic pathways, AßPP first undergoes ß- or α-secretases-mediated cleavages yielding C99 and C83, respectively. These two membrane-embedded C-terminal fragments are both potential targets of subsequent γ-secretase-mediated proteolysis. The latter cleavage not only generates either p3 or Aß peptides but similarly gives rise to an AßPP IntraCellular Domain (AICD fragment) that could modulate the transcription of several genes linked to AD pathology. It is therefore striking that AICD theoretically derives from both amyloidogenic and non-amyloidogenic AßPP processing pathways. Here we show that AICD predominantly derives from C99 by means of recombinant substrates and transiently transfected cells expressing C99. Our data suggest a preferred pathogenic pathway for AICD production and suggests that this fragment, in addition to C99 and Aß peptides, could contribute to AD pathology.

Hippocampal train stimulation modulates recall of fear extinction independently of prefrontal cortex synaptic plasticity and lesions.

It has been shown that long-term potentiation (LTP) develops in the connection between the mediodorsal thalamus (MD) and the medial prefrontal cortex (mPFC) and between the hippocampus (HPC) and the mPFC following fear extinction, and correlates with extinction retention. However, recent lesion studies have shown that combined lesions of the MD and mPFC do not interfere with extinction learning and retention, while inactivation of the dorsal HPC disrupts fear extinction memory. Here we found in rats that immediate post-training HPC low-frequency stimulation (LFS) suppressed extinction-related LTP in the HPC-mPFC pathway and induced difficulties in extinction recall. HPC tetanus, applied several hours later, failed to re-establish mPFC LTP but facilitated recall of extinction. Delayed post-training HPC LFS also provoked mPFC depotentiation and difficulties with extinction recall. HPC tetanus abolished these two effects. We also found that damage to the mPFC induced fear return only in rats that received HPC LFS following extinction training. HPC tetanus also reversed this behavioral effect of HPC LFS in lesioned rats. These data suggest that the HPC interacts with the mPFC during fear extinction, but can modulate fear extinction independently of this interaction.