Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's disease

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Lack of understanding of the fundamental biology driving the early stages of AD may be preventing the development of effective treatments 1. Neuropathological hallmarks of AD – hyperphosphorylated tau neuronal cytoskeletal pathology (Figure 1) and β‐amyloid neuritic plaques – start accumulating in the brain decades before the onset of AD defining symptoms 2. Improving knowledge of early AD biology is an unmet need and is key for the development of disease‐modifying treatments 1.
Tau neuronal cytoskeletal pathology correlates well with neuronal loss and cognitive decline, and its predictable spread into different brain regions serves as the basis for AD staging 4. Therefore, modulating tau neuronal cytoskeletal pathology in the early stages of AD could prevent irreversible neuronal loss and brain damage.
In 1991, Braak and Braak divided the progression of AD into six stages based on the cortical distribution of silver‐stained neuronal cytoplasmic inclusions, called neurofibrillary tangles (NFT) 4. NFT in the transentorhinal/entorhinal cortex and hippocampus characterize stages I and II. Braak stages III–IV are characterized by involvement of limbic areas and the neocortex. NFT develop in primary neocortical areas in Braak stages V–VI 4. The Braak staging system is based on cross‐sectional studies and is rather qualitative, making it challenging to predict when the subject will progress to higher stages or even express symptoms. In fact, multisite workforces are investigating if individuals at low Braak stages represent early AD phases, normal ageing or a mixture of both 5. However, the Braak system is reproducible and correlates well with cognitive status. Finally, a PET‐tau imaging study corroborates the Braak staging system as an indication of AD neuropathological progression 7. We demonstrated that tau cytoskeletal pathology develops in the brainstem's dorsal raphe nucleus (DRN; Figure 2), before the transentorhinal region 8, confirming the DRN's early vulnerability to AD 9. Other studies that investigated the chronological involvement of subcortical structures in AD pathogenesis were examined 11. It became clear that several regions belonging to the isodendritic core – a group of subcortical nuclei with morphologically similar neurons, including the locus coeruleus (LC; Figure 2) and DRN – are involved early in AD 8. The LC shows hyperphosphorylated tau neuronal cytoplasmic inclusions (ht‐NCI) from the fourth decade of life 20. In fact, early isodendritic core degeneration in AD may explain the high prevalence of mood and sleep cycle dysfunction observed in prodromal stages 16. To consolidate these findings, Braak and colleagues revised their original staging system of AD in 2011 to incorporate brainstem structures of the isodendritic core as the earliest involved by sites affected by ht‐NCI 21.
The literature shows conflicting results on the impact of early ht‐NCI formation in the isodendritic core. Also, different authors dispute if ht‐NCI are associated with neuronal loss or are, rather, a more benign epiphenomenon of ageing. For instance, it was suggested that ht‐NCI deposition in brains lacking β‐amyloid deposits should be considered a primary age‐related tauopathy and not early AD 28. A roadblock in clarifying this important question relates to the lack of post mortem brain tissue from well‐characterized individuals at early Braak stages (at prodromal AD phases) and controls because most clinicopathological series come from dementia clinics.
Using a collection of well‐characterized human subjects enriched for controls and early AD stages, we recently demonstrated that the LC shrinks about 8.4% in volume between each Braak stage without a significant loss of neurons until Braak stage III. On the other hand, no changes in LC volume or neuronal counts were seen in normal ageing 31. Furthermore, we found that the rostral third of LC was the most vulnerable to AD pathology, corroborating previous studies 31.

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