ABSTRACT
BACE2 is homologous to BACE1, a beta-secretase that is involved in the amyloidogenic pathway of amyloid precursor protein (APP), and maps to the Down syndrome critical region of chromosome 21. Alzheimer disease neuropathology is common in Down syndrome patients at relatively early ages, and it has thus been speculated that BACE2 co-overexpression with APP would promote the early neurodegenerative phenotype. However, the in vivo function of BACE2 has not yet been elucidated. The aim of the present work has been to analyse the impact of in vivo BACE2 overexpression using a transgenic mouse model. Our results suggest that BACE2 is not involved in the amyloidogenic pathway, cognitive dysfunction or cholinergic degeneration. However, TgBACE2 animals showed increased anxiety-like behaviour along with increased numbers of noradrenergic neurones in locus coeruleus, thus suggesting an unexpected role of BACE2 overexpression.
Subject(s)
Amyloid Precursor Protein Secretases/genetics , Aspartic Acid Endopeptidases/genetics , Alzheimer Disease/enzymology , Alzheimer Disease/genetics , Animals , Anxiety/genetics , Darkness , Down Syndrome/enzymology , Down Syndrome/genetics , Gene Expression Regulation, Enzymologic , Humans , Immunohistochemistry , Locus Coeruleus/pathology , Maze Learning , Mice , Mice, Transgenic , Models, Animal , Motor Activity/genetics , Neurons/pathology , Photosensitivity Disorders/genetics , Prosencephalon/enzymology , RNA/genetics , Transcription, GeneticABSTRACT
Panic disorder is a major cause of medical attention with substantial social and health service cost. Based on pharmacological studies, research on its etiopathogenesis has been focused on the possible dysfunction of specific neurotransmitter systems. However, recent work has related the genes involved in development, synaptic plasticity and synaptic remodeling to anxiety disorders. This implies that learning processes and changes in perception, interpretation and behavioral responses to environmental stimuli are essential for development of complex anxiety responses secondary to the building of specific brain neural circuits and to adult plasticity. The focus of this review is on progress achieved in identifying genes that confer increased risk for panic disorder through genetic epidemiology and the use of genetically modified mouse models. The integration of human and animal studies targeting behavioral, systems-level, cellular and molecular levels will most probably help identify new molecules with potential impact on the pathogenetic aspects of the disease.
