Adverse Stress, Hippocampal Networks, and Alzheimer’s Disease

Abstract

Recent clinical data have implicated chronic adverse stress as a potential risk factor in the development of Alzheimer's disease (AD) and data also suggest that normal, physiological stress responses may be impaired in AD. It is possible that pathology associated with AD causes aberrant responses to chronic stress, due to potential alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Recent work in rodent models of AD suggests that chronic adverse stress exacerbates the cognitive deficits and hippocampal pathology that are present in the AD brain. This review summarizes recent findings obtained in experimental AD models regarding the influence of chronic adverse stress on the underlying cellular and molecular disease processes including the potential role of glucocorticoids. Emerging findings suggest that both AD and chronic adverse stress affect hippocampal neural networks in a similar fashion. We describe alterations in hippocampal plasticity that occur in both chronic stress and AD including dendritic remodeling, neurogenesis and long-term potentiation. Finally, we outline potential roles for oxidative stress and neurotrophic factor signaling as key determinants of the impact of chronic stress on the plasticity of neural networks and AD pathogenesis.

Temporal control of glucocorticoid neurodynamics and its relevance for brain homeostasis, neuropathology and glucocorticoid-based therapeutics

“…On the contrary, stress or corticosterone administration after neurovascular pathology (vasoconstrictioninduced hippocampal ischemia) enhances cognitive recovery in rats (Faraji et al, 2009). In accordance with previous data, chronic stress and elevated GC levels correlate with Aβ amyloid and tau accumulation (Green et al, 2006) as well as with alterations in hippocampal plasticity including dendritic remodelling, neurogenesis and LTP (Rothman and Mattson, 2010). On the contrary, administration of corticosterone in cortical co-cultures of neurons and astrocytes decreases cytosolic Ca 2+ levels in a calmodulin-and GR-dependent manner, counteracting glutamatergic cytotoxic effects due to calcium overload (Suwanjang et al, 2013).…”

Subchronic Glucocorticoid Receptor Inhibition Rescues Early Episodic Memory and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease

“…Although, the presented data and the work from other labs now provide convincing behavioral, biochemical, and electrophysiological evidence that CORT and Ab are intimately linked (Rothman and Mattson, 2010), which one of CORT or Ab accumulation occurs first in our model remains to be fully elucidated. Nevertheless, our data demonstrate that RU486 treatment readily reverses episodic memory and pathologically enhanced LTD present in the early symptomatic phase in our mouse model, thus strongly arguing for a pathological synergistic interaction between chronic APP misprocessing and HPA axis dysregulation.…”

“…Preclinical and clinical data suggest that stress is an important environmental risk factor leading to AD (Rothman and Mattson, 2010). Indeed, patients with a high level of distress proneness are 2.7 times more likely to develop AD, and this trait is also associated with a faster progression of the disease (Wilson et al, 2003(Wilson et al, , 2007.…”

Effects of chronic alcohol consumption on expression levels of APP and Aβ-producing enzymes

“…Brain region-specific changes in the expression of APP processing-related genes may be critical to developing alcohol-induced dementia and AD. The hippocampus, a region of the brain considered critical for learning and memory, appears to be extremely vulnerable in AD (32). Chronic stress and AD cause similar cognitive impairments and pathological hallmarks, specifically in the hippocampus (32).…”