Locus coeruleus at asymptomatic early and middle Braak stages of neurofibrillary tangle pathology

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Alzheimer's disease (AD), the most common cause of cognitive impairment in the elderly, is a progressive neurodegenerative disorder lasting for decades which is characterized morphologically by accumulation of β‐amyloid in the neuropil forming fibrillar diffuse deposits and senile plaques, β‐amyloid deposits in blood vessels leading to amyloid angiopathy and intraneuronal accumulation of hyperphosphorylated and truncated 3Rtau and 4Rtau as the major component of neurofibrillary tangles (NFTs), neuropil threads and dystrophic neurites of senile plaques 1.
These morphological alterations have a particular pattern of distribution which extends to most of the brain along with disease progression 4 paralleling the progressive appearance of clinical symptoms 8. Clinical and pathological changes do not progress in the same way in all individuals; about 85% of the population aged 65 has brain lesions consistent with early changes of AD, yet only about 5% have reached thresholds leading to severe cognitive impairment and dementia (clinical stages of the neurodegenerative process) 11. However, 25% of the population at the age of 85 suffers from dementia of Alzheimer type 12.
The locus coeruleus (LC) is a pontine nucleus containing the largest group of noradrenergic neurons in the central nervous system 13. While the rostral portion of the LC innervates mostly forebrain structures such as the hippocampus and cerebral cortex, the caudal portion innervates mainly hindbrain regions 15. The LC is the only noradrenergic nucleus innervating the cerebral cortex 19, whereas the amygdala also receives projections from the lateral brainstem tegmentum 20. The LC receives input from various regions of the brain 21. All these neuronal networks display the LC as a hub nucleus implicated in superior functions such as arousal, attention, wake–sleep cycles, emotional states, cognition, memory and learning, regulation of blood flow, motor coordination, neuroinflammation, neuronal survival and neurogenesis 14.
Noradrenaline released from the LC acts at specific synapses through α1, α2 or β adrenoceptors 29. Activation of α1 adrenoceptors generally leads to excitation, and there is some evidence that β adrenoceptors are also excitatory. In contrast, activation of α2 adrenoceptors leads to inhibition, including inhibition of the noradrenergic neurons themselves through autoreceptors.
The LC is the main noradrenergic nucleus affected in AD 31. Involvement of the LC at advanced stages of AD has been recognized for decades 14. Considering a percentage of neurone loss of about 70% at terminal stages of the disease 33, it is conceivable that many functions regulated by the LC are severely dampened in advanced AD. However, the LC, together with raphe nuclei, is one the first regions of the brain showing NFTs in the context of AD‐related pathology 38.
Based on this scenario, the present study was focused on the LC at the first asymptomatic Braak stages of NFT pathology in an attempt to (i) define characteristics of tau phosphorylation, configuration and truncation, associated expression of tau kinases, proteins involved in energy metabolism, oxidative stress and responses, tyrosine hydroxylase (TH) immunoreactivity and local synapses in the LC; (ii) assess the impact of these alterations of the LC on the expression of noradrenergic receptors and TH in the hippocampus and amygdala; and (iii) unveil altered gene expression to identify altered pathways in LC associated with early stages of NFT pathology using whole‐transcription arrays.
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