Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal accumulation of β-amyloid and tau and synapse dysfunction in memory-related neural circuits. Pathological and functional changes in the medial temporal lobe, a region essential for explicit memory encoding, contribute to cognitive decline in AD. Surprisingly, functional imaging studies show increased activity of the hippocampus and associated cortical regions during memory tasks in presymptomatic and early AD stages, whereas brain activity declines as the disease progresses. These findings suggest an emerging scenario where early pathogenic events might increase neuronal excitability leading to enhanced brain activity before clinical manifestations of the disease, a stage that is followed by decreased brain activity as neurodegeneration progresses. The mechanisms linking pathology with synaptic excitability and plasticity changes leading to memory loss in AD remain largely unclear. Recent studies suggest that increased brain activity parallels enhanced expression of genes involved in synaptic transmission and plasticity in preclinical stages, whereas expression of synaptic and activity-dependent genes are reduced by the onset of pathological and cognitive symptoms. Here, we review recent evidences indicating a relationship between transcriptional deregulation of synaptic genes and neuronal activity and memory loss in AD and mouse models. These findings provide the basis for potential clinical applications of memory-related transcriptional programs and their regulatory mechanisms as novel biomarkers and therapeutic targets to restore brain function in AD and other cognitive disorders.
Highlights
The rise of life expectancy has profoundly increased the aging population, and the prevalence of age-related cognitive disorders, including Alzheimer’s disease (AD)
We summarize pathological as well as functional features occurring in the brain of human and AD mouse models during aging, and discuss recent evidences suggesting a relationship between gene expression changes and neuronal activity and memory disturbances during the progression of AD
Compared with healthy aged controls, asymptomatic subjects at risk for AD, including presenilin-1 (PSEN1) C410Y and E280A carriers, show higher activation of the hippocampus and frontal and temporal cortices during associative memory encoding years before clinical symptoms (Bassett et al, 2006; Mondadori et al, 2006; Yassa et al, 2008; Reiman et al, 2012). This increase of brain activity seems to reflect a compensatory mechanism to overcome neural dysfunction in preclinical stages, a process that may be necessary for appropriate memory encoding and retrieval (Kircher et al, 2007; O’Brien et al, 2010; Sperling et al, 2010)
Summary
The rise of life expectancy has profoundly increased the aging population, and the prevalence of age-related cognitive disorders, including Alzheimer’s disease (AD). Recent functional imaging studies reveal decreased activity of the MTL in AD patients, whereas function of cortical and temporal lobe regions, the hippocampus, are increased during memory tasks in preclinical and early stages of the disease (i.e., MCI; for review see Sperling et al, 2010). This enhancement of brain activity may represent a compensatory mechanism resulting from reduced neuronal connectivity that can maintain memory encoding at the beginning of the disease process. We summarize pathological as well as functional features occurring in the brain of human and AD mouse models during aging, and discuss recent evidences suggesting a relationship between gene expression changes and neuronal activity and memory disturbances during the progression of AD
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