Neurodegeneration in Alzheimer disease: role of amyloid precursor protein and presenilin 1 intracellular signaling

Abstract

Alzheimer disease (AD) is a heterogeneous neurodegenerative disorder characterized by (1) progressive loss of synapses and neurons, (2) intracellular neurofibrillary tangles, composed of hyperphosphorylated Tau protein, and (3) amyloid plaques. Genetically, AD is linked to mutations in few proteins amyloid precursor protein (APP) and presenilin 1 and 2 (PS1 and PS2). The molecular mechanisms underlying neurodegeneration in AD as well as the physiological function of APP are not yet known. A recent theory has proposed that APP and PS1 modulate intracellular signals to induce cell-cycle abnormalities responsible for neuronal death and possibly amyloid deposition. This hypothesis is supported by the presence of a complex network of proteins, clearly involved in the regulation of signal transduction mechanisms that interact with both APP and PS1. In this review we discuss the significance of novel finding related to cell-signaling events modulated by APP and PS1 in the development of neurodegeneration.

Figure 1

Schematic representation of AβPP processing, the adaptor proteins interacting with its intracellular domain and the pathway leading to ERK1/2 activation. In the left panels is reported the transmembrane protein APP, before and after ITS sequential beta secretase (BACE) and gamma secretase cleavage, with its final products, AICD, APP ectodomain, and beta amyloid peptide (1–40/1–42). In the right part of the figure are indicated the protein interacting with APP intracellular domain, upon or independently from tyrosine phosphorylation. The adaptor proteins Shc and Grb2 through their phosphotyrosine-binding domain (PTB) and src homology domain (SH2) are able to directly bind tyrosine-phosphorylated APP, resulting in the recruitment of the components of the MAP kinase cascade (SoS, ras, Raf, MEK) leading to ERK1/2 activation. Grb2 may participate in this pathway either by direct binding to APP or being recruited by Shc. Alteration in ERK1/2 activity induced in this way may contribute to neurodegeneration in AD. Transduction pathway adaptors (X11, disabled, Fe65, JIP1, and Numb) that bind APP in the absence of tyrosine phosphorylation depicted are also shown.

Figure 2

Schematic representation of the intracellular pathway by which AβPP and PS1 control the activation of the MAPK/ERK1/2 cascade and their final biological effects. In the figure is specified the interaction between APP intracellular domain and PS1 C-terminus, with the adaptor protein Grb2. Grb2 can bind simultaneously to APP and PS1 (as measured in FRET experiments) leading to the MAPK ERK1/2 cascade activation. In AD an aberrant activation of ERK1/2 induced by APP and/or PS1 can determine the tentative activation of the cell cycle that, in postmitotic neurons, may induce cells to undergo apoptosis.

Figure 3

Role of LPR8 activation in normal brain functioning and in neurodegeneration during AD. In the figure are indicated the different roles in which LRP8 transmembrane protein is involved, in the healthy brain and AD pathogenesis.