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      APP processing is regulated by cytoplasmic phosphorylation

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          Abstract

          Amyloid-β peptide (Aβ) aggregate in senile plaque is a key characteristic of Alzheimer's disease (AD). Here, we show that phosphorylation of amyloid precursor protein (APP) on threonine 668 (P-APP) may play a role in APP metabolism. In AD brains, P-APP accumulates in large vesicular structures in afflicted hippocampal pyramidal neurons that costain with antibodies against endosome markers and the β-secretase, BACE1. Western blot analysis reveals increased levels of T668-phosphorylated APP COOH-terminal fragments in hippocampal lysates from many AD but not control subjects. Importantly, P-APP cofractionates with endosome markers and BACE1 in an iodixanol gradient and displays extensive colocalization with BACE1 in rat primary cortical neurons. Furthermore, APP COOH-terminal fragments generated by BACE1 are preferentially phosphorylated on T668 verses those produced by α-secretase. The production of Aβ is significantly reduced when phosphorylation of T668 is either abolished by mutation or inhibited by T668 kinase inhibitors. Together, these results suggest that T668 phosphorylation may facilitate the BACE1 cleavage of APP to increase Aβ generation.

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          Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.

          M S Wolfe, W. Xia, B Ostaszewski … (1999)
          Accumulation of the amyloid-beta protein (Abeta) in the cerebral cortex is an early and invariant event in the pathogenesis of Alzheimer's disease. The final step in the generation of Abeta from the beta-amyloid precursor protein is an apparently intramembranous proteolysis by the elusive gamma-secretase(s). The most common cause of familial Alzheimer's disease is mutation of the genes encoding presenilins 1 and 2, which alters gamma-secretase activity to increase the production of the highly amyloidogenic Abeta42 isoform. Moreover, deletion of presenilin-1 in mice greatly reduces gamma-secretase activity, indicating that presenilin-1 mediates most of this proteolytic event. Here we report that mutation of either of two conserved transmembrane (TM) aspartate residues in presenilin-1, Asp 257 (in TM6) and Asp 385 (in TM7), substantially reduces Abeta production and increases the amounts of the carboxy-terminal fragments of beta-amyloid precursor protein that are the substrates of gamma-secretase. We observed these effects in three different cell lines as well as in cell-free microsomes. Either of the Asp --> Ala mutations also prevented the normal endoproteolysis of presenilin-1 in the TM6 --> TM7 cytoplasmic loop. In a functional presenilin-1 variant (carrying a deletion in exon 9) that is associated with familial Alzheimer's disease and which does not require this cleavage, the Asp 385 --> Ala mutation still inhibited gamma-secretase activity. Our results indicate that the two transmembrane aspartate residues are critical for both presenilin-1 endoproteolysis and gamma-secretase activity, and suggest that presenilin 1 is either a unique diaspartyl cofactor for gamma-secretase or is itself gamma-secretase, an autoactivated intramembranous aspartyl protease.
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            Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations.

            A Cataldo, C Peterhoff, J Troncoso … (2000)
            Endocytosis is critical to the function and fate of molecules important to Alzheimer's disease (AD) etiology, including the beta protein precursor (betaPP), amyloid beta (Abeta) peptide, and apolipoprotein E (ApoE). Early endosomes, a major site of Abeta peptide generation, are markedly enlarged within neurons in the Alzheimer brain, suggesting altered endocytic pathway (EP) activity. Here, we show that neuronal EP activation is a specific and very early response in AD. To evaluate endocytic activation, we used markers of internalization (rab5, rabaptin 5) and recycling (rab4), and found that enlargement of rab5-positive early endosomes in the AD brain was associated with elevated levels of rab4 immunoreactive protein and translocation of rabaptin 5 to endosomes, implying that both endocytic uptake and recycling are activated. These abnormalities were evident in pyramidal neurons of the neocortex at preclinical stages of disease when Alzheimer-like neuropathology, such as Abeta deposition, was restricted to the entorhinal region. In Down syndrome, early endosomes were significantly enlarged in some pyramidal neurons as early as 28 weeks of gestation, decades before classical AD neuropathology develops. Markers of EP activity were only minimally influenced by normal aging and other neurodegenerative diseases studied. Inheritance of the epsilon4 allele of APOE, however, accentuated early endosome enlargement at preclinical stages of AD. By contrast, endosomes were normal in size at advanced stages of familial AD caused by mutations of presenilin 1 or 2, indicating that altered endocytosis is not a consequence of Abeta deposition. These results identify EP activation as the earliest known intraneuronal change to occur in sporadic AD, the most common form of AD. Given the important role of the EP in Abeta peptide generation and ApoE function, early endosomal abnormalities provide a mechanistic link between EP alterations, genetic susceptibility factors, and Abeta generation and suggest differences that may be involved in Abeta generation and beta amyloidogenesis in subtypes of AD.
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              Evidence that production and release of amyloid beta-protein involves the endocytic pathway.

              É Koó, Sharon L Squazzo (1994)
              Amyloid beta-protein (A beta), the 40-43-amino acid polypeptide that is the principal constituent of senile plaques found in Alzheimer's disease, is constitutively produced and released into medium of cultured cells by an unclear mechanism. In this study, we report that one route of A beta generation involves the internalization of cell surface amyloid precursor protein (beta PP) via the coated pit-mediated endocytic pathway. Radiolabeled A beta can be recovered in medium following selective cell surface radioiodination, indicating that cell surface beta PP is a direct precursor to A beta. In addition, deletion of the cytoplasmic domains of beta PP or depletion of potassium in medium, both of which resulted in reduced beta PP internalization, significantly diminished A beta release. Moreover, pulse-chase experiments after surface radioiodination showed that the kinetics of beta PP secretion and A beta release was different, with the latter occurring at a significantly slower rate. We therefore hypothesize that the internalization of cell surface beta PP via coated pit-mediated endocytosis is one pathway leading to A beta generation and release into medium.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cell Biol
                Title: The Journal of Cell Biology
                Publisher: The Rockefeller University Press
                ISSN (Print): 0021-9525
                ISSN (Electronic): 1540-8140
                Publication date (Print): 13 October 2003
                Volume: 163
                Issue: 1
                Pages: 83-95
                Affiliations
                [1 ]Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115
                [2 ]Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
                [3 ]Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478
                [4 ]Department of CNS Discovery, Pfizer Central Research, Groton, CT 06340
                Author notes

                Address correspondence to Li-Huei Tsai, Dept. of Pathology, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Ave., Boston, MA 02115. Tel.: (617) 432-1053. Fax: (617) 432-3975. email: li-huei_tsai@ 123456hms.harvard.edu

                Article
                Publisher ID: 200301115
                DOI: 10.1083/jcb.200301115
                PMC ID: 2173445
                PubMed ID: 14557249
                SO-VID: b6b63fd6-cc14-4a93-9ca1-43d1a32d357d
                Copyright © Copyright © 2003, The Rockefeller University Press
                History
                Date received : 28 January 2003
                Date accepted : 11 August 2003
                Categories
                Subject: Article

                ScienceOpen disciplines: Cell biology
                Keywords: alzheimer's disease; amyloid precursor protein; bace1; endosomes; aβ
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: alzheimer's disease; amyloid precursor protein; bace1; endosomes; aβ

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