Evidence of Aggression in a Mouse Model of Alzheimer’s Disease

Alzheimer’s Disease (AD) is an increasingly prevalent neurodegenerative disorder that is typically recognized for the progressive cognitive dysfunction it induces.  However, agitation, a term covering symptoms of restlessness, irritability, and verbal or physical aggression, is a common AD feature that is present in about one third of patients and becomes more prevalent as the disease advances.  The options available for treating AD agitation are limited.  Only one drug, brexpiprazole, has achieved FDA approval for treating AD agitation. Thus, as the US population continues to age, novel and safer treatments for AD aggression are an increasingly important unmet need.  In rodents, AD aggression can be effectively modeled using the resident intruder test.
 
APP/PS1 mice are a double transgenic strain of mice that feature an accelerated deposition of β-amyloid that can be observed by 12 weeks of age and increased aggression specifically in the male mice.  Aggressive behavior can also be modeled in non-transgenic strains such as CFW mice. Our data demonstrate that treatment with atypical antipsychotics, such as risperidone or brexpiprazole, can attenuate aggressive behavior, as measured by the attack latency and frequency of attack (see Figure, below). 

APP/PS1 mice have increased aggression compared to wild type controls in the resident intruder model, which can be pharmacologically blocked.

Male APP/PS1 mice (20 weeks of age) exhibited lower attack latencies and higher frequency of attacks compared to wild-type littermate controls in the Resident-Intruder aggression test (Panels A and B), suggesting that they were markedly more aggressive. This aggressive phenotype was reversed following acute treatment with Risperidone (Ris) or Compound A (CPDA). Similar patterns of aggression was seen in male CFW mice (Panels C and D) that was significantly attenuated by treatment with risperidone (Ris) or brexpiprazole (Brex).