A perfect storm: Converging paths of epilepsy and Alzheimer's dementia intersect in the hippocampal formation

Jeffrey Noebels
2011 Epilepsia  
Seizures in the human temporal lobe transiently impair cognition and steadily damage hippocampal circuitry, leading to progressive memory loss. Similarly, the toxic accumulation of Aβ peptides underlying Alzheimer's Disease triggers synaptic degeneration, circuit remodeling, and abnormal synchronization within the same networks. Since neuronal hyperexcitability amplifies the synaptic release of Aβ, seizures create a vicious spiral that accelerates cell death and cognitive decline in the AD
more » ... . The confluence of hyperexcitability and excitotoxicity, combined with the challenge of seizure detection in the human hippocampus, make epilepsy in these individuals extremely important to correctly diagnose and treat. Emerging clinical evidence reveals an elevated co-morbidity of epilepsy in AD, particularly when linked to mutations in the APP/Aβ gene pathway. Experimental models in genetically engineered mice confirm and extend these findings, highlighting the presence of subclinical seizures and overlapping pathophysiological cascades. There is an urgent need for more clinical and basic investigation to improve the early recognition of hippocampal seizures arising during the course of dementing disorders, and to validate molecular blockers of Aβ-induced aberrant excitability that can slow and potentially reverse the progression of cognitive decline. The molecular pathology underlying neural degeneration in Alzheimer's Disease has been dramatically clarified over the last decade, however our understanding of the pathogenesis and therapy of human dementia, a foremost clinical problem in our society, is unclear and remains stalled at the level of progressive cell death and altered plasticity at single synapses. Co-morbid conditions such as epilepsy that interfere with memory formation and retrieval in the temporal lobe further complicate the goal of preserving normal cognition. While degenerative processes in the nervous system ultimately result in loss of neural signaling, when active inhibitory mechanisms fail early, the resulting disinhibition may destabilize network oscillatory activity at formative stages of the disease. Critical new evidence implicating cellular hyperexcitablility, hypersynchronous circuit activity, extensive rewiring of hippocampal networks, and subclinical "silent" seizures in the temporal lobe identified in validated mouse models of AD implicates a new level of circuit-based pathophysiology that could lead to the appearance of epilepsy and further aggravate memory loss. Human
doi:10.1111/j.1528-1167.2010.02909.x pmid:21214538 pmcid:PMC3058398 fatcat:tbmfqn4pprcibeamhgeyvybbhm