Neurobiology of cognitive disorders

Abstract

Neurodegenerative brain diseases, including Alzheimer's disease, frontotemporal degeneration and Lewy body disease, are the most frequent pathologies underlying cognitive disorders in old age. This review outlines recent advances in the understanding of key molecular mechanisms involved in these neurodegenerations, particularly with regard to the abnormal processing of proteins. The consequences of these novel insights for therapeutic interventions are also explained. Aberrant processing, misfolding, and subsequent deposition of amyloid beta protein, TAU, alpha-synuclein, and TDP-43 are key events in the pathological cascades of neurodegenerations leading to cognitive impairment and dementia. The nonpolymerized, oligomeric forms of these proteins have neurotoxic properties including the disruption of synaptic function and the induction of oxidative stress. The aggregation and deposition of these proteins may represent a neuronal repair mechanism which ultimately worsens the deleterious effects of the preaggregated forms. Novel disease-modifying treatment strategies aim at down-regulating protein production, inhibiting polymerization, or removing preaggregated forms of the proteins from the brain. Recent research has elucidated important molecular events in neurodegenerative diseases upstream of the aggregation and deposition of proteins which forms their histopathological hallmarks. These insights translate into novel therapeutic strategies which are currently evaluated in clinical trials.