Zebrafish lacking Alzheimer presenilin enhancer 2 (Pen-2) demonstrate excessive p53-dependent apoptosis and neuronal loss.

• Gamma-secretase cleavage, mediated by a complex of presenilin, presenilin enhancer (Pen-2), nicastrin, and Aph-1, is the final proteolytic step in generating amyloid beta protein found in brains of Alzheimer's disease patients and Notch intracellular domain critical for proper neuronal development. Here, we employ the zebrafish model to study the role of Pen-2 in neuronal survival. We found that (i) knockdown of Pen-2 using antisense morpholino led to a reduction of islet-1 positive neurons, (ii) Notch signaling was reduced in embryos lacking Pen-2 or other gamma-secretase components, (iii) neuronal loss in Pen-2 knockdown embryos is not as a result of a lack of neuronal precursor cells or cell proliferation, (iv) absence of Pen-2 caused massive apoptosis in the whole animal, which could be suppressed by simultaneous knockdown of the tumor suppressor p53, (v) loss of islet-1 or acetylated tubulin positive neurons in Pen-2 knockdown embryos could be partially rescued by knockdown of p53. Our results demonstrate that knockdown of Pen-2 directly induces a p53-dependent apoptotic pathway that contributes to neuronal loss and suggest that Pen-2 plays an important role in promoting neuronal cell survival and protecting from apoptosis in vivo.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Psykiatri (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Psychiatry (hsv//eng)

Nyckelord

Alzheimer Disease

Animals

Animals

Genetically Modified

Apoptosis

genetics

Blotting

Northern

Blotting

Western

methods

Body Patterning

drug effects

genetics

Cell Count

methods

Disease Models

Animal

Dose-Response Relationship

Drug

Embryo

Nonmammalian

Fish Proteins

chemistry

deficiency

physiology

Gene Expression Regulation

Developmental

drug effects

genetics

Immunohistochemistry

methods

In Situ Hybridization

methods

In Situ Nick-End Labeling

methods

Indoles

diagnostic use

Membrane Proteins

chemistry

deficiency

metabolism

physiology

Neurons

metabolism

Oligonucleotides

Antisense

pharmacology

Presenilin-2

RNA

Messenger

metabolism

Receptors

Notch

metabolism

Reverse Transcriptase Polymerase Chain Reaction

methods

Tumor Suppressor Protein p53

chemistry

metabolism

Zebrafish

Zebrafish Proteins

deficiency

metabolism

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)