Alzheimer's Disease-Linked Presenilin Mutation (PS1M146L) Induces Filamin Expression and γ-Secretase Independent Redistribution

Article type: Research Article

Authors: Lu, Qun^{a; b; *} | Ding, Kai^c | Frosch, Matthew P.^d | Jones, Shiloh^b | Wolfe, Michael^c | Xia, Weiming^c | Lanford, George W.^b

Affiliations: [a] Harriet and John Wooten Laboratory for Alzheimer's Disease and Neurodegenerative Diseases Research, The Brody School of Medicine, East Carolina University, Greenville, NC, USA | [b] Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA | [c] Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA | [d] C. S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Correspondence: [*] Correspondence to: Qun Lu, PhD., Department of Anatomy and Cell Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA. Tel.: +1 252 744 2844; Fax: +1 252 744 2850; E-mail: [email protected].

Note: [] Handling Associate Editor: Thomas Shea

Abstract: Presenilin mutations are linked to the early onset familial Alzheimer's disease (FAD) and lead to a range of neuronal changes, indicating that presenilins interact with multiple cellular pathways to regulate neuronal functions. In this report, we demonstrate the effects of FAD-linked presenilin 1 mutation (PS1M146L) on the expression and distribution of filamin, an actin cross-linking protein that interacts with PS1 both physically and genetically. By using immunohistochemical methods, we evaluated hippocampal dentate gyrus for alterations of proteins involved in synaptic plasticity. Among many proteins expressed in the hippocampus, calretinin, glutamic acid decarboxylase (GAD67), parvalbumin, and filamin displayed distinct changes in their expression and/or distribution patterns. Striking anti-filamin immunoreactivity was associated with the polymorphic cells of hilar region only in transgenic mice expressing PS1M146L. In over 20% of the PS1M146L mice, the hippocampus of the left hemisphere displayed more pronounced upregulation of filamin than that of the right hemisphere. Anti-filamin labeled the hilar neurons only after the PS1M146L mice reached after four months of age. Double labeling immunohistochemical analyses showed that anti-filamin labeled neurons partially overlapped with cholecystokinin (CCK), somatostatin, GAD67, parvalbumin, and calretinin immunoreactive neurons. In cultured HEK293 cells, PS1 overexpression resulted in filamin redistribution from near cell peripheries to cytoplasm. Treatment of CHO cells stably expressing PS1 with WPE-III-31C or DAPT, selective γ-secretase inhibitors, did not suppress the effects of PS1 overexpression on filamin. These studies support a γ-secretase-independent role of PS1 in modulation of filamin-mediated actin cytoskeleton.

Keywords: Actin, dentate gyrus, filamin, hilar neurons, presenilin mutation, γ-secretase

DOI: 10.3233/JAD-2010-100585

Journal: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 235-245, 2010