The mechanistic link between selective vulnerability of the locus coeruleus and neurodegeneration in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is neuropathologically characterized by the intracellular accumulation of hyperphosphorylated tau and the extracellular deposition of amyloid-β plaques, which affect certain brain regions in a progressive manner. The locus coeruleus (LC), a small nucleus in the pons of the brainstem, is widely recognized as one of the earliest sites of neurofibrillary tangle formation in AD. Patients with AD exhibit significant neuronal loss in the LC, resulting in a marked reduction of its size and function. The LC, which vastly innervates several regions of the brain, is the primary source of the neurotransmitter norepinephrine (NE) in the central nervous system. Considering that NE is a major modulator of behavior, contributing to neuroprotection and suppression of neuroinflammation, degeneration of the LC in AD and the ultimate dysregulation of the LC–NE system has detrimental effects in the brain. In this review, we detail the neuroanatomy and function of the LC, its essential role in neuroprotection, and how this is dysregulated in AD. We discuss AD-related neuropathologic changes in the LC and mechanisms by which LC neurons are selectively vulnerable to insult. Further, we elucidate the neurotoxic effects of LC de-innervation both locally and at projection sites, and how this augments disease pathology, progression and severity. We summarize how preservation of the LC–NE system could be used in the treatment of AD and other neurodegenerative diseases affected by LC degeneration.

Examining the Role of the Noradrenergic Locus Coeruleus for Predicting Attention and Brain Maintenance in Healthy Old Age and Disease: An MRI Structural Study for the Alzheimer’s Disease Neuroimaging Initiative

“…This process might be influenced by manifold variables, such as ageing, the degree of biological brain maintenance and even dementia progression, which is likely to exacerbate this “caudal-shifting” process. Moreover, it is acknowledged how the noradrenergic system is susceptible to compensatory changes across the brain involving the caudal portion of the LC and peri-coeruleus/LC-peri-dendritic regions (Epi-coeruleus and Sub-coeruleus) [ 14 , 54 , 55 , 61 , 103 , 104 , 105 , 106 ]. Therefore, a larger area rather than a very specific and concise region would be more informative and appropriate while investigating the LC–NA system on different groups, particularly known the heterogeneity of Alzheimer’s disease.…”

Examining the Role of the Noradrenergic Locus Coeruleus for 2 Predicting Attention and Brain Maintenance in Healthy Old Age 3 and Disease: An MRI Structural Study for the Alzheimer’s Disease 4 Neuroimaging Initiative

“…The LC has been shown to exhibit early signs of neurodegeneration before the DR nucleus [31], and patients with dementia exhibit significantly reduced Noradrenaline transporters (NET) in the LC but not in the DR [128]. Together these findings suggest that noradrenergic neurons within the DR might provide compensatory support for the broader LC-NA system [128,106,178,180]. Accordingly, the resilience of the DR as a compensatory nucleus to the LC-NA system decay may, in part, explain the observed relationships between DR volume and BrainPAD in the present study.…”

“…Indeed, although the LC shows markers of neurodegeneration years before cognitive decline [101,102], neuronal cell loss in the LC is most appreciable in advanced stages of neurodegeneration rather than in the earlier stages (evidence reported from Braak stage III-IV) [31,101,102,129]. Therefore, throughout the pathological course, the volumetric and functional resilience of the LC (including the maintenance of the surrounding LC-peri dendritic and the epi and sub-coeruleus areas [180,181,14]) may provide a supporting and compensating role in the face of the beta-amyloid pathology occurring in the cortex [101,102,180,190,21,17,16]. Interestingly in this regard, a recent work by Bachman et al [174] found positive relationships between the volume of the LC and surface measures in cortical regions including the rostral medial frontal cortex, which has a high density of noradrenergic varicosities [175].…”

“…This process might be influenced by manifold variables, such as ageing, the degree of biological brain maintenance and even dementia progression, which is likely to exacerbate this "caudal-shifting" process. Moreover, it is acknowledged how the noradrenergic system is susceptible to compensatory changes across the brain involving the caudal portion of the LC and peri-coeruleus/LC-peri-dendritic regions (Epi-coeruleus and Sub-coeruleus) [106,128,177,178,180,181,182,14]. Therefore, considering a larger area rather than a very specific and concise region would be more informative and appropriate while investigating the LC-NA system on different groups, particularly known the heterogeneity of Alzheimer's Disease.…”

“…In addition, noradrenergic drugs which increase LC activity and cognitive performances might be beneficial [134,135,136,137]. Studies using noradrenergic drugs showed that interventions ameliorated AD-like pathology and partially re-stored noradrenergic tone in humans [134,135,180]. However, the benefit of noradrenergic drugs is controversial and side effects should be considered while evaluating this approach (see Holland et al (2021) for a review) [172].…”