Date of Degree
Nikolaos K. Robakis
Biology | Neuroscience and Neurobiology
Aβ pathology, Alzheimer’s disease, brain derived neurotrophic factor, cognitive impairment, neurodegeneration, neurogenesis, neurotrophic factor, mortality, synaptic plasticity, tau pathology, therapeutic prevention, 3xTg-AD
Studies described in this thesis deal with the preventive effects of a neurogenic/neurotropic peptidergic compound, P021, on neurogenesis and synaptic deficits, neurodegeneration, cognitive impairment, and Ab and tau pathologies in a 3xTg-AD mouse model of Alzheimer’s disease (AD).
Background: AD is a chronic progressive neurodegenerative disease. Its multifactorial nature and the heterogeneity make its treatment especially challenging. Although it is a major burden in society, at present there is no drug that can stop or slow down the progression of the disease. Currently, the only available treatments are symptomatic and for mild to severe stages. The development of a drug that can prevent AD at its early stages would be of major importance. The use of neurotrophic factors mimetic for the treatment of AD is an exciting therapeutic strategy. It focuses mainly on boosting synaptic plasticity and neurogenesis which lead to shifting the balance from neurodegeneration to regeneration of the brain as well as preventing Ab and tau pathologies. Herein, I present the preventive effects of P021 treatment in 3xTg-AD mice that is initiated very early in the disease during the period of synaptic compensation and is continued for the lifespan of the animal.
Aims: The specific aims were: 1) to study the presence of the synaptic compensation phenomenon in the brain as a self-repairing mechanism in 3xTg-AD mice; 2) to study the preventive effects of P021 on cognitive deterioration when administered during the compensation period; 3) to study the preventive effects of P021 on amyloid beta (Ab) and tau pathologies; and 4) to study the effect of P021 on synaptic deficit, neuronal degeneration and neurogenesis.
Methods: A battery of behavioral tests was conducted to assess the cognitive performance in 3xTg-AD mice with and without treatment with P021 at different disease stages. Immunohistochemical and biochemical analyses were performed to determine the levels of synaptic protein expression as well as Ab and tau pathologies at different time points that correspond to different stages of disease progression. Neurodegeneration was studied immunohistochemically with Fluorojade C staining. Neurogenesis was studied immunohistochemically with DCX (double cortin) and Ki-67 staining.
Results: The 3xTg-AD mice at the age of 12 weeks were found to be cognitively impaired and showed a decrease in multiple synaptic and neuronal markers. This decrease was compensated by the brain until ~16 weeks of age. Beyond 16 weeks the brain was found to fail to compensate for the synaptic deficit. P021 intervention, started at 14 weeks of age, prevented cognitive impairment 9 months post-treatment, as tested by the Morris Water maze task. At 15-17 months post-treatment P021 was able to rescue short-term spatial reference memory as well as episodic memory, as determined by the novel object location and the novel object recognition tasks. The treatment with P021 also prevented Ab and tau pathologies during 9-18 months post-treatment. P021 was able to rescue synaptic deficit and neurodegeneration 9-18 months post-treatment and boost neurogenesis at 9 months post-treatment. P021 treatment increased survival from 41% in 3xTg-AD-vh to 87% in 3xTg-AD-P021 mice. In the entire study I did not find any severe side effects of P021 including loss of appetite or body weight.
Conclusions: Early intervention with P021 during the period of synaptic compensation of the brain was successful in preventing cognitive impairment in 3xTg-AD mice. The P021 treatment prevented synaptic and neurogenesis deficits, neurodegeneration, and Ab and tau pathologies. These findings provide a proof of principle of the potential therapeutic effect of P021 on several major features of AD.
Baazaoui, Narjes, "Effect of CNTF Derived Peptide, P021 on Cognition and Pathology in 3xTG-AD Mouse Model of Alzheimer's Disease" (2016). CUNY Academic Works.