Conditional Depletion of Hippocampal Brain-Derived Neurotrophic Factor Exacerbates Neuropathology in a Mouse Model of Alzheimer’s Disease

David J. Braun, Sergey Kalinin, Douglas L. Feinstein

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Damage occurring to noradrenergic neurons in the locus coeruleus (LC) contributes to the evolution of neuroinflammation and neurodegeneration in a variety of conditions and diseases. One cause of LC damage may be loss of neurotrophic support from LC target regions. We tested this hypothesis by conditional unilateral knockout of brain-derived neurotrophic factor (BDNF) in adult mice. To evaluate the consequences of BDNF loss in the context of neurodegeneration, the mice harbored familial mutations for human amyloid precursor protein and presenilin-1. In these mice, BDNF depletion reduced tyrosine hydroxylase staining, a marker of noradrenergic neurons, in the rostral LC. BDNF depletion also reduced noradrenergic innervation in the hippocampus, the frontal cortex, and molecular layer of the cerebellum, assessed by staining for dopamine beta hydroxylase. BDNF depletion led to an increase in cortical amyloid plaque numbers and size but was without effect on plaque numbers in the striatum, a site with minimal innervation from the LC. Interestingly, cortical Iba1 staining for microglia was reduced by BDNF depletion and was correlated with reduced dopamine beta hydroxylase staining. These data demonstrate that reduction of BDNF levels in an LC target region can cause retrograde damage to LC neurons, leading to exacerbation of neuropathology in distinct LC target areas. Methods to reduce BDNF loss or supplement BDNF levels may be of value to reduce neurodegenerative processes normally limited by LC noradrenergic activities.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalASN Neuro
Volume9
Issue number2
DOIs
StatePublished - Mar 1 2017

Bibliographical note

Publisher Copyright:
© 2017, © The Author(s) 2017.

Keywords

  • adeno-associated virus
  • Alzheimer’s disease
  • amyloid
  • brain-derived neurotrophic factor
  • locus coeruleus
  • neuroinflammation
  • neurotrophin
  • noradrenaline
  • tyrosine hydroxylase

ASJC Scopus subject areas

  • Neuroscience (all)
  • Clinical Neurology

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