An experimental model of Braak’s pretangle proposal for the origin of Alzheimer’s disease: the role of locus coeruleus in early symptom development

Abstract

Background The earliest brain pathology related to Alzheimer’s disease (AD) is hyperphosphorylated soluble tau in the noradrenergic locus coeruleus (LC) neurons. Braak characterizes five pretangle tau stages preceding AD tangles. Pretangles begin in young humans and persist in the LC while spreading from there to other neuromodulatory neurons and, later, to the cortex. While LC pretangles appear in all by age 40, they do not necessarily result in AD prior to death. However, with age and pretangle spread, more individuals progress to AD stages. LC neurons are lost late, at Braak stages III–IV, when memory deficits appear. It is not clear if LC hyperphosphorylated tau generates the pathology and cognitive changes associated with preclinical AD. We use a rat model expressing pseudohyperphosphorylated human tau in LC to investigate the hypothesis that LC pretangles generate preclinical Alzheimer pathology. Methods We infused an adeno-associated viral vector carrying a human tau gene pseudophosphorylated at 14 sites common in LC pretangles into 2–3- or 14–16-month TH-Cre rats. We used odor discrimination to probe LC dysfunction, and we evaluated LC cell and fiber loss. Results Abnormal human tau was expressed in LC and exhibited somatodendritic mislocalization. In rats infused at 2–3 months old, 4 months post-infusion abnormal LC tau had transferred to the serotonergic raphe neurons. After 7 months, difficult similar odor discrimination learning was impaired. Impairment was associated with reduced LC axonal density in the olfactory cortex and upregulated β1-adrenoceptors. LC infusions in 14–16-month-old rats resulted in more severe outcomes. By 5–6 months post-infusion, rats were impaired even in simple odor discrimination learning. LC neuron number was reduced. Human tau appeared in the microglia and cortical neurons. Conclusions Our animal model suggests, for the first time, that Braak’s hypothesis that human AD originates with pretangle stages is plausible. LC pretangle progression here generates both preclinical AD pathological changes and cognitive decline. The odor discrimination deficits are similar to human odor identification deficits seen with aging and preclinical AD. When initiated in aged rats, pretangle stages progress rapidly and cause LC cell loss. These age-related outcomes are associated with a severe learning impairment consistent with memory decline in Braak stages III–IV. Electronic supplementary material The online version of this article (10.1186/s13195-019-0511-2) contains supplementary material, which is available to authorized users.

Correlation between cognition and plasma noradrenaline level in Alzheimer’s disease: a potential new blood marker of disease evolution

“…Most of the noradrenergic neurons in the CNS originate from the locus coeruleus (LC) and project to different areas of the brain, such as the cortex, hippocampus, amygdala, thalamus, and hypothalamus 10 . Hyperphosphorylation of Tau protein in the LC appears at an early stage of AD pathogenesis 11 , and the number of neurons in the LC has been shown to progressively decrease during the disease, beginning at the prodromal stage of AD 8,[12][13][14][15][16][17] . Based on the current literature, one of the ideas that has emerged is that the onset of AD is preceded by abnormal hyperactivation of the LC, resulting in oversecretion of NA in the cortex 18 .…”

A probabilistic atlas of locus coeruleus pathways to transentorhinal cortex for connectome imaging in Alzheimer's disease

“…The revised Braak staging of AD pathology proposes that tau pathology responsible for the pathogenesis of AD occurs first in the LC and propagates from there to the TEC and other brain regions ( Braak et al, 2011 ). Evidence from recent animal ( de Calignon et al, 2012 ; Ghosh et al, 2019 ; Liu et al, 2012 ) and human brain imaging studies ( Cope et al, 2018 ; Franzmeier et al, 2019 ; Hoenig et al, 2018 ; Jacobs et al, 2018a ; Jones et al, 2017 ) also support the hypothesis of cell-to-cell propagation of tau pathology along axonal pathways ( Braak and Del Tredici, 2011 ). Given these emerging findings, it would be valuable to map the fiber pathways from the LC nuclei to the TEC in order to evaluate the potentially earliest changes in brain connectivity due to tau pathology in AD.…”

Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer’s disease

“…With increasing age, abnormal tau appears in a characteristic topographical sequence in noradrenergic projection targets like the mediotemporal lobe (referred to as Braak stages, a classification system of the progression of tau spread; Braak et al, 2011; Chalermpalanupap, Weinshenker, & Rorabaugh, 2017; Stratmann et al, 2016). An animal model indicates that injecting hyperphosphorylated human tau into the rodent LC leads to its slow spread to other brainstem nuclei and eventually to cortical regions (Ghosh et al, 2019).…”

“…LC degeneration, however, does not only constitute a consequence of Alzheimer’s pathology but also contributes to its disease development (Marien, Colpaert, & Rosenquist, 2004; Mather & Harley, 2016; Satoh & Iijima, 2019; Weinshenker, 2018). Studies with genetically modified animals indicate that abnormally phosphorylated tau in the LC leads to dysfunctional noradrenergic neuromodulation in memory-relevant brain areas (Ghosh et al, 2019; Rorabaugh et al, 2017; Weinshenker, 2018) and that tau pathology and LC degeneration synergistically aggravate neural and behavioral deterioration (Chalermpalanupap et al, 2018; also see Jacobs, Riphagen, Ramakers, & Verhey, 2019). Specifically, experimentally decreased norepinephrine levels have been associated with increased tau and amyloid-β deposition, another hallmark of AD (Chalermpalanupap et al, 2018; Heneka et al, 2010).…”