Intraneuronal beta-amyloid accumulation in the amygdala enhances fear and anxiety in Alzheimer's disease transgenic mice

Biol Psychiatry. 2010 Mar 15;67(6):513-21. doi: 10.1016/j.biopsych.2009.06.015. Epub 2009 Aug 7.


Background: Alzheimer's disease (AD) is characterized by progressive memory decline and neuropsychiatric symptoms. Despite common emotional symptoms in AD such as anxiety and fear are associated with a more rapid cognitive decline, the pathological mechanisms involved in these behavioral changes remain largely elusive. In this study, we examined the pathological mechanisms of emotional behavior in well-established AD transgenic mice expressing human mutant beta-amyloid (Abeta) precursor protein (APP(Ind) and APP(Sw,Ind)) and tau (3xTg-AD).

Methods: We evaluated unconditioned and conditioned fear-induced freezing behavior and spatial memory in APP(Ind), APP(Sw,Ind), and 3xTg-AD transgenic mice. The Abeta and tau pathologies and signaling pathways involved in emotional processing were studied by immunohistochemistry and immunoblotting analyses.

Results: The APP(Ind)/APP(Sw,Ind) and 3xTg-AD transgenic mice displayed at early ages enhanced innate and conditioned fear symptoms and spatial memory deficits coinciding with enhanced accumulation of Abeta in gamma-aminobutyric acid (GABA)ergic and glutamatergic neurons, respectively, of the basolateral amygdala (BLA). Similarly, the number of neurons with intraneuronal Abeta40 and Abeta42 was significantly increased in the BLA of human AD brains. Fear responses might reflect an influence of anxiety, because the anxiolytic compounds valproate, diazepam, and buspirone reduced efficiently unconditioned and conditioned fear responses in APP transgenic mice. In addition, phosphorylation of extracellular signal-regulated kinase (ERK)1/2, which is critical for acquisition and consolidation of fear conditioning, was increased in the amygdala of APP transgenic mice after cued conditioning.

Conclusions: We propose a deleterious role of intraneuronal Abeta on amygdala-dependent emotional responses by affecting the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / complications*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amygdala / metabolism*
  • Amygdala / pathology
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Anxiety / drug therapy
  • Anxiety / etiology*
  • Conditioning, Classical / physiology
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Enzyme Inhibitors / therapeutic use
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fear / drug effects
  • Fear / psychology*
  • Female
  • Gene Expression Regulation / genetics
  • Humans
  • Male
  • Memory Disorders / etiology
  • Memory Disorders / metabolism
  • Memory Disorders / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • Peptide Fragments / metabolism
  • Polycomb-Group Proteins
  • Presenilin-1 / genetics
  • Signal Transduction / physiology
  • Statistics, Nonparametric
  • Transcription Factors / metabolism
  • Valproic Acid / therapeutic use
  • tau Proteins / genetics


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • PHF1 protein, human
  • PSEN1 protein, human
  • Peptide Fragments
  • Polycomb-Group Proteins
  • Presenilin-1
  • Transcription Factors
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Valproic Acid
  • Extracellular Signal-Regulated MAP Kinases