An animal model of early Alzheimer’s disease pathogenesis in the interoceptive-allostatic network

Project Summary
Although cognitive detriments are the hallmark of Alzheimer’s disease (AD), increasing evidence demonstrates
that people with AD experience significant changes to their affective lives as well. Neurobiological investigations
of AD have focused heavily on understanding pathology in the cognitive hubs of the brain, although some
evidence exists points to similar structural, cellular, and synaptic pathology in hubs of the interoceptive-allostatic
network that generates and regulates affect. The proposed work will investigate neuropathogenesis in the
interoceptive-allostatic network in our highly translatable nonhuman primate model of early AD pathogenesis.
AD pathology is thought to begin with the generation of abnormal oligomeric proteins (amyloid beta oligomers,
AβOs) from misprocessed amyloid precursor protein. AβOs are toxic to synapses, and over time AβO buildup
and synaptic damage are thought to lead to deposition of amyloid plaques and formation of hyperphosphorylated
tau protein causing neurofibrillary tangles and neuronal loss, the hallmarks of AD neuropathology. We have
demonstrated that exogenous administration of AβOs to middle-aged rhesus monkeys causes synapse loss
targeted to highly plastic thin dendritic spines and neuroinflammation in cognitive neural hubs, changes that
mirror what is thought to occur in the earliest prodromal phase of human AD. We are currently carrying out a
large-scale study which tracks cognitive and affective behavior as AβOs are administered to monkeys over time.
The proposed research will build on that existing resource by carrying out detailed neuroimaging and histological
analyses of the interoceptive-allostatic network in order to understand how AβOs damage neural hubs that
generate and regulate affect. The proposed experiments are innovative because they evaluate early AD-related
pathology in the network that generates affect. These experiments will allow us to develop AβO administration
in rhesus monkeys as a model for testing interventions that may derail the progression of pathological cascades
before full-blown AD develops, providing a new setting for developing treatments for an urgent public health
problem.

Grant Number: 4RF1AG078340-02
NIH Institute/Center: NIH
Principal Investigator: Eliza Bliss-Moreau