Metabolism of Alzheimer’s Disease: systems and cellular networks

ABSTRACT
Alzheimer's disease (AD) is increasing in prevalence in the United States and despite efforts to date an effective
treatment remains elusive. AD presents clinically as amyloid plaque load, neurofibrillary tangles comprised of
hyper phosphorylated tau, and abnormal vasculature, but the mechanistic basis for cognitive decline is not
known. We have shown that the anti-aging intervention of caloric restriction (CR) preserves brain volume and
neuronal synaptic density, and lowers age-related astrogliosis. Importantly, age-related shifts in redox
metabolism and mitochondrial energy metabolism in brain are abrogated by CR. Our hypothesis is that
neuroprotection by CR will slow AD pathology development specifically through its impact on brain metabolism.
We will implement CR in APP PS1 (amyloid plaques) and hTauP301 (neurofibrillary tangles) mouse models of
AD to determine the impact of CR-induced changes in brain metabolism on pathology development and the
consequence for cellular networks of neurons, glia, and the vasculature. Experiments include behavioral testing,
ex vivo electrophysiology, and in vivo imaging technology. Brain metabolism will be tracked using histochemistry
and 2-photon metabolic imaging. Additional mechanistic studies using pharmacological and genetic approaches
in primary neurons and astrocytes will determine the impact of metabolism on brain cell-cell networks. There are
three specific aims:
Specific Aim 1: To determine the impact of CR on AD pathology advance, documenting hippocampal
dependent memory and behaviors, ex vivo measures of synaptic transmission and hippocampal neuronal
networks, and brain metabolism.
Specific Aim 2: To determine the impact of metabolism and AD pathology on neuron-glial crosstalk using
co-cultured primary neurons and primary astrocytes. Live imaging studies will investigate how neurons with
amyloidopathy and tauopathy respond to changes in astrocyte metabolism in real time.
Specific Aim 3: To determine the in vivo impact of CR-induced changes in brain metabolism and AD
pathology on vascular responsivity and adaptation using implanted transparent electrodes and opto-genetics
coupled with coherence tomography.
These studies focus on the interaction between disease pathology and the local brain metabolic
environment, acknowledging the importance of layers of communication among neuronal, neuron-glia, and
vascular networks, and establishing mechanisms behind the neuroprotective effects of CR. The proposed
research will advance our understanding of the role metabolism plays in AD progression, and will determine if
strategies to preserve brain metabolism as a function of age might have therapeutic potential as a means to
ameliorate outcomes of AD, translating basic biology to clinical promise.

Grant Number: 5R01AG067330-05
NIH Institute/Center: NIH
Principal Investigator: Rozalyn Anderson