Project 2 of the Johns Hopkins Alzheimer's Disease Research Center (ADRC) is titled "Modeling an anti-amyloid therapy for AD: potential for cognitive recovery". This project focuses the role of oligomeric amyloid-beta (A-beta) peptides in the cognitive impairment associated with Alzheimer's disease (AD). The 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 outcomes of therapeutic interventions that target A-beta production will inform appropriate expectations in clinical trials.
Understanding mechanisms that influence the pathology of Alzheimer's disease, and whether it is possible to reduce pathology once it has developed, is of crucial importance in developing strategies to combat Alzheimer's disease, a neurodegenerative disorder which affects over 6 million Americans.
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