Modeling an anti-amyloid therapy for AD
Principal Investigator: Alena Savonenko, M.D., Ph.D.
The presence of oligomeric amyloid-beta (A-beta) peptides in the brain has been associated with cognitive impairment in mouse models of Alzheimer's disease. This project will test the hypothesis that accumulation of oligomeric A-beta species impairs learning and memory and that these cognitive impairments can be reversed with suppression of A-beta generation. To address this question we will use a mouse model of A-beta amyloidosis in which the expression of mutant amyloid precursor protein (APP) is controlled by a tetracycline-regulated promoter (these transgenic mice are known as TetOffAPP mice). A-beta production can be suppressed in these mice with doxycycline. Preliminary data suggest that following A-beta suppression with doxycycline, amyloid deposits are stable but there is, nevertheless, a gradual amelioration of the memory deficits. This finding has led to the following three specific aims:
(1) Aim 1: To determine whether the reduction of oligomoeric A-beta species derived from newly-synthesized A-beta peptides improves learning and memory in the conditional TetOffAPP mouse models after genetically induced arrest of APP expression and new A-beta production.
(2) Aim 2: To determine whether recovery of synaptic damage is associated with cognitive improvement after A-beta production; synaptic, glutamatergic and immediate early gene markers of neuronal activity will be assessed in mice with significant amelioration of memory deficits.
(3) Aim 3: To examine the role of neurodegenerative changes in CNS monoamine systems in relation to the degree of cognitive recovery observed after reduction of A-beta peptides in the TetOffAPP mice. Collectively, outcomes from these studies will address an important issue regarding the value of an anti-amyloid therapeutic strategy for AD by assessing the magnitude of functional repair and recovery after synaptic damage by oligomeric A-beta. Evaluation of the outcome of therapeutic interventions that target A-beta production will inform appropriate expectations in clinical trials.
For more information, contact Alena Savonenko at email@example.com.