Diego Sepulveda-falla

University of Hamburg, Institute of Neuropathology, UKE, Junior Group Leader

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Bora Gurel

Kocaeli University

Dominic D'Agostino

University of South Florida

David Vago

Vanderbilt University

Mike Williamson

The University of Sheffield

niha ansari

Gujarat Technological University

Prof Henry Ademola Adeola

University of Cape Town

Andrea Chiba

University of California, San Diego

Kai Skaftnesmo

University of Bergen

Michael Geusz

Bowling Green State University

Simona Ruta

University of Medicine and Pharmacy "Carol Davila" Bucharest

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Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

by Diego Sepulveda-falla and Luis Velazquez-perez

Journal of Clinical Investigation, 2014

onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases ... more onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A-associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca 2+ channels IP3Rs and CACNA1A were downregulated, and Ca 2+ -dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/ mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca 2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration. Familial Alzheimer's disease (FAD) is a rare variant of Alzheimer's disease (AD), the most common form of dementia, which is characterized by early onset (<65 years old), increased severity, and autosomal dominant inheritance of mutations in amyloid precursor protein (APP), presenilin-1 (PS1), and PS2 (1). PS1 mutations, of which around 180 have been described, account for 80% of all FAD cases (2). There is wide clinical variability in PS1-FAD, including epileptic seizures and cerebellar ataxia. At the neuropathological level, brain tissue of PS1-FAD patients shows characteristic β-amyloid (Aβ) plaque morphology and localized damage such as cerebellar degeneration (3, 4). An interesting FAD mutation is PS1-E280A (E280A-FAD), which is present in a large kindred in Colombia with more than 5,000 members and around 600 affected individuals. Apart from common FAD symptoms, such as epilepsy and ataxia, E280A-FAD patients show typical clinical endophenotypes, including aphasia and variable age of onset (5). PS1 provides the catalytic core of the γ-secretase complex, which is involved in amyloidogenic processing of APP, which defines the length of the Aβ peptide (6, 7). PS1 mutations can increase the ratio of longer Aβ peptides, which are more prone to aggregation and show higher neurotoxicity (8). On the other hand, independent from its role in the γ-secretase complex, PS1 may contribute to several other functions, including protein turnover (9), autophagy (10), and ER Ca 2+ regulation (11). Up to which point these functions participate in the pathogenesis of FAD remains to be elucidated.

Diego Sepulveda-falla

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