Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model.

Bibliographic

Year of Publication: 
2018
Contact PI Name: 
Rudolph E Tanzi
Contact PI Affiliation: 
Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
Co-Authors: 
SH Choi, E Bylykbashi, ZK Chatila, SW Lee, B Pulli, GD Clemenson, E Kim, A Rompala, MK Oram, C Asselin, J Aronson, C Zhang, SJ Miller, A Lesinski, JW Chen, DY Kim, H van Praag, BM Spiegelman, FH Gage
Primary Reference (PubMED ID): 
Funding Source:
Study Goal and Principal Findings: 

Adult hippocampal neurogenesis (AHN) is impaired before the onset of Alzheimer’s disease (AD) pathology. We found that exercise provided cognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN and elevating levels of brain-derived neurotrophic factor (BDNF). Neither stimulation of AHN alone, nor exercise, in the absence of increased AHN, ameliorated cognition. We successfully mimicked the beneficial effects of exercise on AD mice by genetically and pharmacologically inducing AHN in combination with elevating BDNF levels. Suppressing AHN later led to worsened cognitive performance and loss of preexisting dentate neurons. Thus, pharmacological mimetics of exercise, enhancing AHN and elevating BDNF levels, may improve cognition in AD. Furthermore, applied at early stages of AD, these mimetics may protect against subsequent neuronal cell death.

Therapeutic Agent

Therapeutic Information: 
Therapy Type:
Therapy Type:

Animal Model

Model Information: 
Species:
Model Type:
Strain/Genetic Background: 
C57BL6/SJL

Experimental Design

Is the following information reported in the study?: 
Power/Sample Size Calculation
Blinded for Treatment
Pharmacokinetic Measures
Toxicology Measures
Biomarkers
Formulation
Duration of Treatment
Age of Animal at the Beginning of Treatment
Sex as a Biological Variable
Number of Premature Deaths
Statistical Plan
Inclusion/Exclusion Criteria Included
Randomized into Groups
Blinded for Outcome Measures
Pharmacodynamic Measures
ADME Measures
Dose
Route of Delivery
Frequency of Administration
Age of Animal at the End of Treatment
Study Balanced for Sex as a Biological Variable
Number of Excluded Animals
Genetic Background
Conflict of Interest

Experiment Notes

Inclusion/Exclusion criteria are detailed in the supplemental information.

Outcomes

Outcomes: 
Outcome MeasuredOutcome Parameters
Behavioral
  • Delayed Nonmatching to Place (DNMP)
  • Exploratory Activity
  • Locomotion
  • Radial Arm Maze
  • Spontaneous Alternation
  • Y Maze
  • Histopathology
  • beta amyloid deposits
  • beta amyloid load
  • Microgliosis
  • Neuronal Loss
  • phospho-Tau
  • Biochemical
  • Brain-Derived Neurotrophic Factor (BDNF)
  • Interferon (IFN) gamma
  • IL-1 beta
  • IL-2
  • IL-4
  • IL-5
  • IL-6
  • IL-10
  • IL-12p70
  • Postsynaptic Density Protein 95 (PSD95)
  • Synapse-Associated Protein 97 (SAP97)
  • Synaptophysin
  • Tumor Growth Factor beta (TGF beta)
  • Tumor Necrosis Factor alpha (TNF alpha)
  • Fibronectin Type III Domain-Containing Protein 5 (FNDC5)
  • Keratinocyte Chemoattractant/Growth-Regulated Oncogene (KC/GRO)
  • Immunochemistry
  • Brain-beta amyloid deposits
  • BrdU
  • Caspase 3
  • Cleaved Caspase 3
  • Cell Proliferation
  • Doublecortin (DCX)
  • Glial Fibrillary Acidic Protein (GFAP)
  • Ionized Calcium Binding Adaptor Molecule 1 (Iba1)
  • Neuronal Marker NeuN
  • phospho-Tau
  • Microscopy
  • Dendritic Arborization
  • Dendritic Length
  • Dendritic Spine Density
  • Neuronal Cell Number
  • Neuronal Loss
  • Stereology
  • Cell Biology
  • Cell Viability
  • FACS Analysis