Early loss of locus coeruleus innervation promotes cognitive and neuropathological changes before amyloid plaque deposition in a transgenic rat model of Alzheimer's disease

Abstract

Aims: The locus coeruleus (LC) is the main source of noradrenaline (NA) in the mammalian brain and has been found to degenerate during the initial stages of Alzheimer's disease (AD). Recent studies indicate that at late stages of the amyloid pathology, LCpathological alterations accelerate AD-like pathology progression by interfering with the neuromodulatory and anti-inflammatory properties of NA. However, the impact of LC degeneration at the earliest stages of amyloidosis on the AD-like pathology is not well understood. Methods: The LC was lesioned in wild-type and McGill-R-Thy1-APP transgenic (APP tg) rats by administering N-(2-chloroethyl)-N-ethyl-bromo-benzylamine before amyloid plaque deposition. Cognitive deficits and AD-like neuropathological changes were measured after the LC lesion.Results: Four months post-treatment, rats displayed a decrease in brain noradrenergic innervation. The LC lesion in APP tg-treated rats enhanced cognitive deficits and decreased hippocampal cholinergic innervation and neurotrophin expression. In addition, the APP tg-treated rats displayed an increased microglial and astroglial cell number in close vicinity to hippocampal amyloid-beta burdened neurons. The recruited microglia showed cellular alterations indicative of an intermediate activation state. Conclusions:Our results indicate that early LC demise aggravates the early neuroinflammatory process, cognitive impairments, cholinergic deficits and neurotrophin deregulation at the earliest stages of the human-like brain amyloidosis.

Evidence for a novel neuronal mechanism driving Alzheimer's disease, upstream of amyloid

“…Braak et al., (2011) 10 identified a pre‐tangle stage consisting of an accumulation of hyperphosphorylated tau (p‐tau) in the LC, while β‐amyloid is absent, with neuronal loss occurring caudally at this site 10 ; a similar occurrence of tau pathology again without any β‐amyloid has been reported elsewhere in the brainstem 3 . Data from animal studies validate these findings by showing that a chemical lesion of the LC in the APP transgenic mouse model induces AD neuropathological changes before β‐amyloid plaque deposition 11 . Similarly, infusion of pseudo‐hyperphosphorylated human tau into the LC of rats, results in a spread of pre‐tangle tau to other IC nuclei (e.g., dorsal raphe) and eventually to cortical areas 12 .…”

“… 3 Data from animal studies validate these findings by showing that a chemical lesion of the LC in the APP transgenic mouse model induces AD neuropathological changes before β‐amyloid plaque deposition. 11 Similarly, infusion of pseudo‐hyperphosphorylated human tau into the LC of rats, results in a spread of pre‐tangle tau to other IC nuclei (e.g., dorsal raphe) and eventually to cortical areas. 12 Studies on individuals with mutations in genes causing autosomal‐dominant AD provide an excellent opportunity to investigate preclinical changes in vivo: in such cases, the decline of LC integrity is independent of β‐amyloid, is negatively correlated with cortical damage and memory loss, and starts up to 12 years before the clinical onset.…”

The Effect of Fat Intake with Increased Omega-6-to-Omega-3 Polyunsaturated Fatty Acid Ratio in Animal Models of Early and Late Alzheimer’s Disease-like Pathogenesis

“…This is an occurrence that is frequent in most transgenic models. In recent reports, it has been documented that about 50% of homozygous McGill-R-Thy1-APP rats display plaques at 12 months of age [22][23][24]. In addition, at 6-month-old, homozygous McGill-R-Thy1-APP rats show increased intermediate activated microglia in the subiculum, and by 13 months of age, the increment in activated microglia is observed throughout the cortex and the hippocampal formation [25].…”

Selective Noradrenaline Depletion in the Neocortex and Hippocampus Induces Working Memory Deficits and Regional Occurrence of Pathological Proteins

“…Tau manifests at the early stages of AD in LC, and from there it spreads throughout the brain as the disease progresses [ 27 , 28 ]. Converging evidence indicates that early alterations in the structure and function of the noradrenergic system contribute to the neuropathological alterations observed in rodent models of AD [ 29 , 30 ]. Modeling these changes in experimental animals would certainly be of great value in the quest for viable therapeutic strategies.…”

“…There is scant preclinical evidence about the possible relationships between altered amyloid expression in the neocortex/hippocampus and reduced neurotransmission, the latter generally referring to cholinergic inputs from the basal forebrain neurons [ 31 , 32 , 33 , 34 , 35 , 36 ]. Interestingly, recent evidence indicates that early alterations in the structure and function of the noradrenergic system may also affect amyloid expression in rodent models of AD [ 29 , 30 ]. However, not much experimental work has addressed the possible effects of early noradrenergic loss on other neuropathological hallmarks of AD, such as regional expression of hyperphosphorylated Tau and/or TDP-43.…”