Acute stress increases interstitial fluid amyloid-β via corticotropin-releasing factor and neuronal activity

Abstract

Aggregation of the amyloid-␤ (A␤) peptide in the extracellular space of the brain is critical in the pathogenesis of Alzheimer's disease. A␤ is produced by neurons and released into the brain interstitial fluid (ISF), a process regulated by synaptic activity. To determine whether behavioral stressors can regulate ISF A␤ levels, we assessed the effects of chronic and acute stress paradigms in amyloid precursor protein transgenic mice. Isolation stress over 3 months increased A␤ levels by 84%. Similarly, acute restraint stress increased A␤ levels over hours. Exogenous corticotropin-releasing factor (CRF) but not corticosterone mimicked the effects of acute restraint stress. Inhibition of endogenous CRF receptors or neuronal activity blocked the effects of acute stress on A␤. Thus, behavioral stressors can rapidly increase ISF A␤ through neuronal activity in a CRF-dependent manner, and the results suggest a mechanism by which behavioral stress may affect Alzheimer's disease pathogenesis.Alzheimer's disease ͉ synaptic activity ͉ environmental stress ͉ microdialysis ͉ transgenic E vidence indicates that the aggregation and accumulation of the amyloid-␤ (A␤) peptide in the brain extracellular space is a key initiating event in the pathogenesis of Alzheimer's disease (AD) (1). A number of studies demonstrate that aggregation of A␤ is concentration-dependent (2). Increasing the amount of A␤ produced by 50% or specifically increasing the more fibrillogenic A␤ 42 either by APP gene dose or mutations in amyloid precursor protein (APP), PS1, or PS2, accelerates the onset of A␤ deposition and AD (3). Conversely, decreasing A␤ by decreasing cleavage of APP or by enhancing clearance of A␤ delays the onset of A␤ deposition (4). Thus, determining factors that regulate the levels of A␤ in the brain extracellular space, where it likely changes conformation and aggregates, may provide insight into AD pathogenesis and treatment.A␤ is produced in the brain primarily by neurons after cleavage of APP by ␤-and ␥-secretase (1). A␤ levels in the extracellular space are then influenced by factors regulating its release from neurons as well as postsecretory events such as transport and clearance. Recent evidence (5, 6) has shown that A␤ release from neurons is regulated by neuronal and specifically synaptic activity over minutes to hours. However, whether behavioral manipulations regulate synaptic activity and interstitial fluid (ISF) A␤ levels has not been addressed.Evidence in both humans and animals suggests that environmental stressors may increase risk for AD or AD pathology. In humans, persons without dementia who are prone to psychological distress are more likely to develop AD (7,8). Also, plasma levels of the stress hormone, cortisol, are correlated with the rate of dementia progression in patients with AD (9). In mouse models of AD, animals subjected to isolation stress over months had decreased learning performance and accelerated A␤ deposition (10). To explore the potential mechanisms and links between behavioral stressors and A...

Stress Acts Cumulatively To Precipitate Alzheimer's Disease-Like Tau Pathology and Cognitive Deficits

“…The etiology of late-onset, sporadic (nonfamilial) forms of Alzheimer's disease (AD) is largely unknown, but there is growing consensus that lifetime events such as environmental stressors may increase the probability of risk for the disease (Wilson et al, 2003;Csernansky et al, 2006;Kang et al, 2007). This view is supported by reports of hypersecretion of stress hormones [glucocorticoids (GCs)] in AD patients (Hartmann et al, 1997;Weiner et al, 1997;Elgh et al, 2006), and indications that psychological distress may cause mild cognitive impairment (Wilson et al, 2003) and predispose affected individuals to AD (Wilson et al, 2007).…”

“…Stress, whose effects are mediated by GCs, is a plausible causal agent (Wilson et al, 2003;Csernansky et al, 2006;Kang et al, 2007). Clinical studies show a relationship between GC levels and severity of symptoms (Miller et al, 1998) and suggest that high GC levels accelerate disease progression (Csernansky et al, 2006).…”

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

“…AD transgenic mouse models are characterized by Aβ plaque formation and this leads to decreased cell proliferation and defective contextual memory (Kang et al 2007). APP, the precursor protein to Aβ, is O-GlcNAc-modified although the importance of this modification remained elusive for many years (Jacobsen and Iverfeldt 2011).…”

Systematic Analysis of GWAS Data Reveals Genomic Hotspots for Shared Mechanisms between Neurodegenerative Diseases

“…The complex also enhances neuronal activity by interacting with adenylate cyclase, cAMP, act(PAK), Ca2 signaling pathways [41]. The resulting enhanced neuronal activity has been shown to further accumulate interstitial fluid amyloid beta (ISF Aβ), while this accumulation of ISF Aβ is also linked with up-regulation of CRH gene expression [42], effectively establishing a feedback loop that can enhance negative dysregulation events. MAPT hyper-phosphorylation also increases its dissociation from microtubules, a process that has been linked to lewy-bodies and Parkinsonism, in the PD context [43].…”