Turning on the Light Within: Subcortical Nuclei of the Isodentritic Core and their Role in Alzheimer's Disease Pathogenesis

Abstract

Pharmacological interventions in Alzheimer's disease (AD) are likely to be more efficacious if administered early in the course of the disease, foregoing the spread of irreversible changes in the brain. Research findings underline an early vulnerability of the isodendritic core (IC) network to AD neurofibrillary lesions. The IC constitutes a phylogenetically conserved subcortical system including the locus coeruleus in pons, dorsal raphe nucleus, and substantia nigra in the midbrain, and nucleus basalis of Meynert in basal forebrain. Through their ascending projections to the cortex, the IC neurons regulate homeostasis and behavior by synthesizing aminergic and cholinergic neurotransmitters. Here we reviewed the evidence demonstrating that neurons of the IC system show neurofibrillary tangles in the earliest stages of AD, prior to cortical pathology, and how this involvement may explain pre-amnestic symptoms, including depression, agitation, and sleep disturbances in AD patients. In fact, clinical and animal studies show a significant reduction of AD cognitive and behavioral symptoms following replenishment of neurotransmitters associated with the IC network. Therefore, the IC network represents a unique candidate for viable therapeutic intervention and should become a high priority for research in AD.

Keywords: Aging; Alzheimer’s disease; brainstem nuclei; early diagnosis; human; monoamines; neurodegeneration; neurofibrillary tangles; neuromodulation; pathology.

Figure 1

The human isodentritic core network extends from the brainstem to the basal forebrain. (A) Ventral (left) and dorsal (right) views of the human brainstem, depicting the caudal midbrain (i) and the rostral (ii) and mid-pons (iii) at the rostrocaudal axis. (B) 3D reconstruction of the isodentritic core nuclei in the brainstem. Despite their relative small size on the horizontal plane, each nucleus occupies large areas within the brainstem's core. Note the overlapping between the structures as well as the idiosyncrasy of their shape and location. The transparent surface represents the brainstem boundaries; green, orange and blue represent the substantia nigra, the dorsal raphe nucleus and the locus coeruleus, respectively. (C–F) Delineation of the isodentritic core nuclei in thick histological sections (300 μm) of the human brainstem and the basal forebrain stained with gallocyanin (Nissl). (C) Locus coeruleus situated laterally to the midline and ventrally to the fourth ventricle in the pons. (D) The dorsal raphe nucleus is located medially in the midbrain ventrally to the aqueduct. (E) The substantia nigra extends bilaterally in the rostral and caudal midbrain, dorsally to the cerebral peduncles. (F) The spatial arrangement of the subnuclei of the nucleus basalis of Maynert in a horizontal section through the left hemisphere. Ayala: Ayala's nucleus; Ch4 al, nucleus basalis of Meynert anterolateral part; Ch4 am: nucleus basalis of Meynert, anteromedial part; Ch4 i: nucleus basalis of Meynert, intermediate part; Ch4 p: nucleus basalis of Meynert, posterior part. Scale bars: (A) 1 cm, (C–F) 1 mm.

Figure 2

Immunostaining against hyperphosphorylated tau in the isodentritic core nuclei of the brainstem. Thin paraffin sections (5 μm) from the substantia nigra (A), locus coeruleus (B) and dorsal raphe nucleus (C) show prominent neurofibrillary lesions in Alzheimer's disease brains. Insets correspond to the framed areas and show neurofibrillary tangles (arrow) and threads (arrowhead). Scale bars: 200 μm, Insets 20 μm.