Abstract
Amyloid precursor protein (APP) is processed along both the nonamyloidogenic pathway preventing amyloid beta peptide (Aβ) production and the amyloidogenic pathway, generating Aβ, whose accumulation characterizes Alzheimer’s disease. Items of evidence report that the intracellular trafficking plays a key role in the generation of Aβ and that the 37/67 kDa LR (laminin receptor), acting as a receptor for Aβ, may mediate Aβ-pathogenicity. Moreover, findings indicating interaction between the receptor and the key enzymes involved in the amyloidogenic pathway suggest a strong link between 37/67 kDa LR and APP processing. We show herein that the specific 37/67 kDa LR inhibitor, NSC48478, is able to reversibly affect the maturation of APP in a pH-dependent manner, resulting in the partial accumulation of the immature APP isoforms (unglycosylated/acetylated forms) in the endoplasmic reticulum (ER) and in transferrin-positive recycling endosomes, indicating alteration of the APP intracellular trafficking. These effects reveal NSC48478 inhibitor as a novel small molecule to be tested in disease conditions, mediated by the 37/67 kDa LR and accompanied by inactivation of ERK1/2 (extracellular signal-regulated kinases) signalling and activation of Akt (serine/threonine protein kinase) with consequent inhibition of GSK3β.
Highlights
The accumulation of amyloid beta peptide (Aβ) in the brain is a neuropathological hallmark of Alzheimer’s disease (AD) [1]
In order to evaluate the possible effects of NSC48478 on Amyloid precursor protein (APP) levels, as well as on APP posttranslational modifications, we employed the neuronal GT1 cells we had previously used to investigate prion protein and 37/67 kDa laminin receptor (LR) trafficking under the use of receptor inhibitors [30]
APP migrated on SDS-PAGE gel as a typical glycosylated protein, showing different bands ranging from ~110 to ~135 kDa (Figure 1A), as already reported for other cell types [28]
Summary
The accumulation of amyloid beta peptide (Aβ) in the brain is a neuropathological hallmark of Alzheimer’s disease (AD) [1]. Aβ is produced by a sequential processing of amyloid precursor protein (APP) by β- and γ-secretases [2,3]. A large body of evidence suggests that the production of Aβ occurs in the endo/lysosomal pathway where APP physiologically traffics [4] and where γ-secretases are preferentially distributed [5,6]. An aberrant production of Aβ in AD brains could amplify its neurotoxic effects through activation of GSK3β (Glycogen synthase kinase 3 beta) [19]. The neurotoxic Aβ peptide has been shown to activate GSK3β in hippocampal neurons and to cause cell death [20]—an event that is blocked by introduction of antisense oligonucleotides to GSK3β [21]
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