The brain’s shield against Alzheimer’s disease
Alzheimer’s disease is a progressively debilitating neurodegenerative disorder with no modifying therapies available. The key pathophysiological event is the accumulation in the brain of neurotoxic amyloid beta, which is released from the beta-amyloid precursor protein (APP) during specialised processing events. Interestingly, mature APP is significantly reduced in the human cerebellum compared to entorhinal cortex and hippocampus. Presenilin 2 (PS2) is overexpressed in the cerebellum compared to other parts of the brain, indicating that it might be responsible for the reduced amyloid beta generation. Scientists of the EU-funded BRAINPROTECT (Presenilin 2 - a protector against Alzheimer's disease) project investigated the protective role of PS2 against Alzheimer’s disease and possibly other neurodegenerative disorders. They worked under the hypothesis that the cerebellum contains factors that protect this part of the brain from Alzheimer’s disease. To identify the mechanisms underlying neurodegeneration, they compared Alzheimer’s disease with the neurodegenerative condition Niemann-Pick type C disease (NPC), which primarily affects the Purkinje neurons in the cerebellum. Molecular and cellular analysis of in vitro and in vivo models of these two diseases revealed interesting information on the role of PS2 and its homologue PS1. In the mouse model of NPC disease, the C-terminal levels of PS2 were significantly increased in the rest of the brain while PS1 was higher in the rest of the brain. These observations indicated that PS1 and PS2 proteins may have different functions in different regions of the brain: PS1 mediating faster or PS2 mediating slower cell death events. Therefore, increased PS2 protein levels in human cerebellum may serve as a resilience factor in the resistance of cerebellum to Alzheimer’s disease pathology. Overall, the results suggested that selective modulation of PS2 could increase the brain’s protection against neurodegeneration. This is expected to contribute to the design of novel therapeutic strategies for the successful treatment of neurodegenerative disorders with obvious socioeconomic impact.
Keywords
Alzheimer’s disease, neurodegenerative disorder, cerebellum, presenilin 2, BRAINPROTECT, Niemann-Pick type C disease
