Search for unknown neural link between the masticatory and cognitive brain systems to clarify the involvement of its impairment in the pathogenesis of Alzheimer's disease

Abstract

Brain degenerations in sporadic Alzheimer's disease (AD) are observed earliest in the locus coeruleus (LC), a population of noradrenergic neurons, in which hyperphosphorylated tau protein expression and β-amyloid (Aβ) accumulation begin. Along with this, similar changes occur in the basal forebrain cholinergic neurons, such as the nucleus basalis of Meynert. Neuronal degeneration of the two neuronal nuclei leads to a decrease in neurotrophic factors such as brain-derived neurotrophic factor (BDNF) in the hippocampus and cerebral cortex, which results in the accumulation of Aβ and hyperphosphorylated tau protein and ultimately causes neuronal cell death in those cortices. On the other hand, a large number of epidemiological studies have shown that tooth loss or masticatory dysfunction is a risk factor for dementia including AD, and numerous studies using experimental animals have also shown that masticatory dysfunction causes brain degeneration in the basal forebrain, hippocampus, and cerebral cortex similar to those observed in human AD, and that learning and memory functions are impaired accordingly. However, it remains unclear how masticatory dysfunction can induce such brain degeneration similar to AD, and the neural mechanism linking the trigeminal nervous system responsible for mastication and the cognitive and memory brain system remains unknown. In this review paper, we provide clues to the search for such "missing link" by discussing the embryological, anatomical, and physiological relationship between LC and its laterally adjoining mesencephalic trigeminal nucleus which plays a central role in the masticatory functions.

Keywords: 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL); Alzheimer’s disease; locus coeruleus; mesencephalic trigeminal nucleus; neurotrophic factor-3 (NT-3).

Figure 1

Location of nerve nuclei in a coronal section of the rat brainstem (Bregma, −9.68 mm; Paxinos and Watson, 1996). From medial to lateral, Locus coeruleus (LC), mesencephalic trigeminal nucleus (MTN), and medial part of the parabrachial nucleus (MPB) are located adjacent to each other.

Figure 2

Relationship between the LC-MTN-PBN neural circuit and the basal forebrain (BF), cortex (Cx) and hippocampus (Hipp). LC projections to MTN and PBN exert excitatory and inhibitory effects through the activation of α2A adrenergic receptor (AR), respectively. LC also projects to BF. Glutamatergic PBN is the core nucleus of the ascending arousal system, and activates MN and the bed nucleus stria terminalis (BNST) that activates LC. The activity of γ-motoneurons (γMN) produces neurotrophic factor NT-3 in muscle spindles, which is transported retrogradely to MTN and subsequently can be paracrine secreted from MTN. The viability of Cx and Hipp cells is maintained by noradrenergic (NA) and cholinergic (ACh) inputs, while conversely AD develops due to the impairment of LC and BF.

Figure 3

Primary sensory neuron mode. A functional mode that faithfully transmits the impulse activity arising from muscle spindles to α-motoneurons (αMN). Precise masticatory movements are possible.

Figure 4

Premotor neuron mode. When MTN neurons receive NA input from LC and glutamatergic input from central nucleus of the amygdala (CeA) at the same time, MTN neurons act as premotor neurons that fire in bursts and thereby powerfully drive αMN, without impulses from muscle spindles (MS), to perform biting attacks and predatory activities. Glutamate receptor (GluR) current is enhanced by inhibition of h-current (I_h) as a result of activation of α2A AR by LC inputs (Kawasaki et al., 2018; Toyoda et al., 2022).

Figure 5

When MTN neurons act as primary sensory neurons, secretory NT-3 produced by muscle spindles (MS) is taken up by endocytosis after binding to TrkC receptors expressed in the axon terminal and transported retrogradely as endosomes through the axon to the cell body of the MTN neuron, from which NT-3 can be further paracrine released to the LC.

Figure 6

When MTN neurons function as premotor neurons, there is no replenishment of NT-3 from muscle spindles (MS). Then, NT-3 would be finally depleted after secretion of NT-3, without replenishment, by the bursting activity of MTN neurons evoked by coactivation of LC and CeA.