Locus coeruleus cellular and molecular pathology during the progression of Alzheimer’s disease

Abstract

A major feature of Alzheimer’s disease (AD) is the loss of noradrenergic locus coeruleus (LC) projection neurons that mediate attention, memory, and arousal. However, the extent to which the LC projection system degenerates during the initial stages of AD is still under investigation. To address this question, we performed tyrosine hydroxylase (TH) immunohistochemistry and unbiased stereology of noradrenergic LC neurons in tissue harvested postmortem from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI, a putative prodromal AD stage), or mild/moderate AD. Stereologic estimates of total LC neuron number revealed a 30% loss during the transition from NCI to aMCI, with an additional 25% loss of LC neurons in AD. Decreases in noradrenergic LC neuron number were significantly associated with worsening antemortem global cognitive function as well as poorer performance on neuropsychological tests of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. Reduced LC neuron numbers were also associated with increased postmortem neuropathology. To examine the cellular and molecular pathogenic processes underlying LC neurodegeneration in aMCI, we performed single population microarray analysis. These studies revealed significant reductions in select functional classes of mRNAs regulating mitochondrial respiration, redox homeostasis, and neuritic structural plasticity in neurons accessed from both aMCI and AD subjects compared to NCI. Specific gene expression levels within these functional classes were also associated with global cognitive deterioration and neuropathological burden. Taken together, these observations suggest that noradrenergic LC cellular and molecular pathology is a prominent feature of prodromal disease that contributes to cognitive dysfunction. Moreover, they lend support to a rational basis for targeting LC neuroprotection as a disease modifying strategy.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0411-2) contains supplementary material, which is available to authorized users.

The Longevity of Hippocampus-Dependent Memory Is Orchestrated by the Locus Coeruleus-Noradrenergic System

“…In a recent study, patients with amnestic mild cognitive impairment exhibited a 30% loss of neuronal cells in the LC [75]. Those patients may have a prodromal stage of Alzheimer's disease.…”

Locus Coeruleus Ablation Exacerbates Cognitive Deficits, Neuropathology, and Lethality in P301S Tau Transgenic Mice

“…Degeneration of the noradrenergic brainstem locus coeruleus (LC) is an early and ubiquitous feature of AD that correlates well with many of its other elements, such as ␤-amyloid (A␤) plaques, tau neurofibrillary tangles, and cognitive impairment (Iversen et al, 1983;Mann, 1983;Bondareff et al, 1987;Chan-Palay and Asan, 1989;Haglund et al, 2006;Grudzien et al, 2007). Norepinephrine (NE) is important for many AD-relevant behaviors and cognitive functions (e.g., arousal, attention, affective behaviors, learning, and memory) in addition to having anti-inflammatory and neuroprotective properties (Szabadi, 2013;Feinstein et al, 2016;Mather and Harley, 2016). Thus, as the sole source of NE to critical AD-associated brain regions, such as the hippocampus and frontal cortex, damage to the LC likely contributes to disease progression and severity (Mann, 1983;Zweig et al, 1989;Jalbert et al, 2008;Gannon et al, 2015).…”

“…Norepinephrine (NE) is important for many AD-relevant behaviors and cognitive functions (e.g., arousal, attention, affective behaviors, learning, and memory) in addition to having anti-inflammatory and neuroprotective properties (Szabadi, 2013;Feinstein et al, 2016;Mather and Harley, 2016). Thus, as the sole source of NE to critical AD-associated brain regions, such as the hippocampus and frontal cortex, damage to the LC likely contributes to disease progression and severity (Mann, 1983;Zweig et al, 1989;Jalbert et al, 2008;Gannon et al, 2015).…”

Anin vivoProbabilistic Atlas of the Human Locus Coeruleus at Ultra-high Field

“…The LC neurons degenerate in many neurological disorders. For example, abnormal pre-tangle tau protein is detected in the LC in Alzheimer’s disease from the earliest stages (Braak et al, 2011, Grudzien et al, 2007, Kelly et al, 2017), and severe cell loss is observed in Alzheimer’s disease, Parkinson’s disease and Progressive Supranuclear Palsy (Theofilas et al, 2017, Surmeier et al, 2017, Kaalund et al, 2020). Dysregulation of the LC noradrenergic system has been associated with clinical symptoms and cognitive impairments in neurodegenerative disorders (Weinshenker, 2008, Kehagia et al, 2010, Passamonti et al, 2018a).…”