Locus Coeruleus and neurovascular unit: From its role in physiology to its potential role in Alzheimer’s disease pathogenesis

Sep 3, 2020Journal of neuroscience research

The Locus Coeruleus and Brain Blood Flow System: From Normal Function to Possible Roles in Alzheimer's Disease

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Abstract

Locus coeruleus degeneration is linked to early changes in Alzheimer's disease pathology.

The Locus coeruleus is the main source of noradrenaline in the brain, which plays a role in various brain functions.
Degeneration of the Locus coeruleus may contribute to the progression of Alzheimer's disease through noradrenaline loss.
The neurovascular unit (NVU) consists of neurons, glial cells, and blood vessels, and is essential for regulating blood flow and energy supply in the brain.
Alterations in the NVU are associated with Alzheimer's disease, potentially leading to reduced blood flow and disrupted blood-brain barrier integrity.
Loss of modulation by the Locus coeruleus may influence neuroinflammation and amyloid plaque accumulation, both of which are implicated in Alzheimer's disease.
Limited experimental studies have directly investigated the mechanisms linking Locus coeruleus lesions to Alzheimer’s disease pathology.

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Locus coeruleus (LC) is the main noradrenergic (NA) nucleus of the central nervous system. LC degenerates early during Alzheimer's disease (AD) and NA loss might concur to AD pathogenesis. Aside from neurons, LC terminals provide dense innervation of brain intraparenchymal arterioles/capillaries, and NA modulates astrocyte functions. The term neurovascular unit (NVU) defines the strict anatomical/functional interaction occurring between neurons, glial cells, and brain vessels. NVU plays a fundamental role in coupling the energy demand of activated brain regions with regional cerebral blood flow, it includes the blood-brain barrier (BBB), plays an active role in neuroinflammation, and participates also to the glymphatic system. NVU alteration is involved in AD pathophysiology through several mechanisms, mainly related to a relative oligoemia in activated brain regions and impairment of structural and functional BBB integrity, which contributes also to the intracerebral accumulation of insoluble amyloid. We review the existing data on the morphological features of LC-NA innervation of the NVU, as well as its contribution to neurovascular coupling and BBB proper functioning. After introducing the main experimental data linking LC with AD, which have repeatedly shown a key role of neuroinflammation and increased amyloid plaque formation, we discuss the potential mechanisms by which the loss of NVU modulation by LC might contribute to AD pathogenesis. Surprisingly, thus far not so many studies have tested directly these mechanisms in models of AD in which LC has been lesioned experimentally. Clarifying the interaction of LC with NVU in AD pathogenesis may disclose potential therapeutic targets for AD.

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Locus Coeruleus and neurovascular unit: From its role in physiology to its potential role in Alzheimer’s disease pathogenesis

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