Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Aβ42, and Tau in Nuclear Roles

Abstract

Amyloid precursor protein (APP) metabolites (amyloid-β (Aβ) peptides) and Tau are the main components of senile plaques and neurofibrillary tangles, the two histopathological hallmarks of Alzheimer disease. Consequently, intense research has focused upon deciphering their physiological roles to understand their altered state in Alzheimer disease pathophysiology. Recently, the impact of APP metabolites (APP intracellular fragment (AICD) and Aβ) and Tau on the nucleus has emerged as an important, new topic. Here we discuss (i) how AICD, Aβ, and Tau reach the nucleus and how AICD and Aβ control protein expression at the transcriptional level, (ii) post-translational modifications of AICD, Aβ, and Tau, and (iii) what these three molecules have in common.

Keywords: Alzheimer disease; DNA-protein interaction; Tau protein (Tau); amyloid precursor protein (APP); amyloid-beta (AB); gene regulation; gene transcription.

FIGURE 1.

Proteolytic processing of full-length APP (flAPP) into AICD and Aβ. Single α- or β-cleavages of full-length APP release the soluble APP forms (sAPPα or sAPPβ). The respective C-terminal α- and β-stubs are cleaved by γ-secretase (at ϵ-cleavage sites; see also Fig. 2) or the β-stub is cleaved by consecutive α-/γ secretase cuts to produce AICDs and p3. AICD49–99 corresponds to Aβ42, and AICD50–99 corresponds to Aβ40. CTF, CCAAT box-binding transcription factor.

FIGURE 2.

Partial amino acid sequence of the APP C-terminal fragment. The main cleavage sites of α-, β-, and γ-secretases are indicated by the respective Greek letters, the APP transmembrane sequence (TMS) is highlighted in yellow, the amino acid numbers are referring to the Aβ sequence, and the blue bar indicates residues of Aβ42. The multiple cleavages indicated by arrows and numbers occur from the C- to the N-terminal direction in a precursor-product cascade exerted by the γ-secretase complex (49, 50). The major processing routes converge at Aβ34, which is further hydrolyzed into Aβ30 (50). The N-terminal half of the TMS of APP is stabilized the GXXXG interaction motif with Gly-29 and Gly-33 (in red) as the central residues (51, 96, 97). In addition to familial mutations (98), e.g. T43I (11), TMS interactions affect the ϵ-cut exerted by the γ-secretase and shift the ratio of the two AICD species between the Aβ42 (AICD 49–99) and the Aβ40 product line (AICD 50–99). The hydrophobicity in the core of the APP GXXXG motif determines dimer stability, and specific substitutions in interactions sites (e.g. T43V) can stabilize dimerization of C-terminal fragments, which favors the production of Aβ42 and AICD 49–99 (51).

FIGURE 3.

Schematic representation of the AICD/Aβ/Tau nuclear localization. In neuronal cell nuclei, Tau can bind to and protect DNA. Stress-induced dephosphorylation (circled P) increases the nuclear level of Tau and its binding to DNA. Aβ peptides of varying lengths such as Aβ38, Aβ40, Aβ42, and Aβ43 are internalized by cells and detected in the nucleus. The Aβ42 peptide specifically interacts with gene regulatory elements and provokes changes in gene transcription similar to AICD either as a repressor or as an activator of transcription. AICD was reported to translocate with the adapter protein Fe65 into the nucleus where it forms the AFT complex including the histone acetyltransferase Tip60.