Alteration of Neural Pathways and Its Implications in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease accompanied by cognitive and behavioral symptoms. These AD-related manifestations result from the alteration of neural circuitry by aggregated forms of amyloid-β (Aβ) and hyperphosphorylated tau, which are neurotoxic. From a neuroscience perspective, identifying neural circuits that integrate various inputs and outputs to determine behaviors can provide insight into the principles of behavior. Therefore, it is crucial to understand the alterations in the neural circuits associated with AD-related behavioral and psychological symptoms. Interestingly, it is well known that the alteration of neural circuitry is prominent in the brains of patients with AD. Here, we selected specific regions in the AD brain that are associated with AD-related behavioral and psychological symptoms, and reviewed studies of healthy and altered efferent pathways to the target regions. Moreover, we propose that specific neural circuits that are altered in the AD brain can be potential targets for AD treatment. Furthermore, we provide therapeutic implications for targeting neuronal circuits through various therapeutic approaches and the appropriate timing of treatment for AD.

Keywords: Alzheimer’s disease; connectome; neural circuits; neural pathways; neurodegeneration.

Figure 1

Schematic diagram of the hippocampal efferent pathways indicating projection patterns for the target regions: the yellow arrows represent the outputs from CA1; the green arrows indicate the outputs from CA2; the red arrows indicate the outputs from CA3; the purple arrows indicate the subiculum output; and the solid cyan line shows higher-order pathways. Abbreviations: AM—anteromedial thalamic nucleus; AON—anterior olfactory nucleus; AV—anteroventral thalamic nucleus; BLA—basolateral amygdala; EC—entorhinal cortex; LHA—lateral hypothalamic area; OFC—orbitofrontal cortex; LS—lateral septal nuclei; MB—mammillary bodies; MS/DB—medial septum/diagonal band of Broca nuclei; MRN—median raphe nucleus; NAc—nucleus accumbens; PFC—prefrontal cortex; POR—postrhinal cortex; PRC—perirhinal cortex; PVN—paraventricular nucleus; RE—nucleus reuniens of the thalamus; RSC—retrosplenial cortex; SNc—substantia nigra pars compacta; Sub—subiculum; SuM—supramammillary nucleus; VTA—ventral tegmental area.

Figure 2

Schematic diagram of septal outputs indicating projection patterns from the LS and MS/DB to the target regions. The yellow, blue, and red arrows represent the cholinergic, glutamatergic, and GABAergic pathways from the MS/DB, respectively. Green arrows indicate LS projections. Abbreviations: AHN, anterior hypothalamic nucleus; CC, cingulate cortex; DG, dentate gyrus; DMH, dorsomedial hypothalamic nucleus; EC, entorhinal cortex; LHA, lateral hypothalamic area; LS, lateral septal nuclei; MB, mammillary body; MHb, medial habenula; MS/DB, medial septum/diagonal band of Broca nuclei; OB, olfactory bulb; PC, piriform cortex; PH, posterior hypothalamic nucleus; POA, preoptic area; PT, paratenial nucleus; PVH, paraventricular hypothalamic nucleus; PVT, paraventricular thalamus; RE, nucleus reuniens; RSC, retrosplenial cortex; Sub, subiculum; VMH, ventromedial hypothalamus; VTA, ventral tegmental area.

Figure 3

Schematic diagram of the noradrenergic (NA) pathway from the LC to various regions, such as the neocortex, pallidal regions, thalamus, hypothalamus, hippocampal formation, brainstem, and cerebellum. The thickness of the arrow indicates the degree of connectivity. A1—primary auditory cortex; ACC—anterior cingulate cortex; ARC—arcuate nucleus; BLA—basolateral amygdala; CN—cochlear nucleus; CRN—caudal raphe nuclei; DG—dentate gyrus; DRN—dorsal raphe nuclei; EW—Edinger–Westphal nucleus; FN—facial nucleus; HGN—hypoglossal nucleus; LDT—laterodorsal tegmental nuclei; LHb—lateral habenula; M1—primary motor cortex; MNG—midline nuclear group; MOB—main olfactory bulb; mPFC—medial prefrontal cortex; MS—medial septum; NVmt—trigeminal motor nucleus; NVsnpr—trigeminal sensory nucleus; OFC—orbitofrontal cortex; ONC—oculomotor nuclear complex; PeFLH—lateral hypothalamus/perifornical area; PPT—pedunculopontine tegmental nuclei; PVN—paraventricular nucleus; RVLM—rostral ventrolateral medulla; SI—substantia innominate; SN—salivatory nuclei; VA—ventral anterior nuclei; VLPO—ventrolateral preoptic area; VPL—ventral posterolateral nucleus; VPM—ventral posteromedial nucleus; vSub—ventral subiculum.

Figure 4

Schematic diagram showing each dopaminergic pathway and GABAergic pathway from the SN to the target regions. The substantia nigra pars compacta (SNc) sends dopaminergic projections to the striatum, hippocampus, and brainstem. The substantia nigra pars reticular (SNr) provides GABAergic projections to the thalamus and brainstem. The solid cyan line shows higher-order cortical pathways. ACC—anterior cingulate cortex; CN—caudate nucleus; DLPFC—Dorsolateral prefrontal cortex; MD—mediodorsal nucleus; ORC—orbitofrontal cortex; PF—parafascicular nucleus; pmRF—pontomedullary reticular formation; PPT—pedunculopontine tegmental nucleus; SC—superior colliculus; TRN—thalamic reticular nucleus; VPL—ventral posterolateral nucleus; VA—ventral anterior nuclei; VL—ventral lateral nucleus; VPM—ventral posteromedial nucleus.

Figure 5

Schematic diagram of visual efferent pathways indicating projection patterns from the retina to brain regions: the solid black lines represent the pathways from the retina to the retinorecipient regions; the solid purple line indicates the geniculate pathway; and the solid orange line shows the colliculo-pulvinar pathway. dLGN—dorsal lateral geniculate nucleus; dMTN—dorsal medial terminal nucleus; DSGCs—direction-selective ganglion cells; IGL—intergeniculate leaflet; ipRGCs—intrinsically photosensitive retinal ganglion cells; NOT-DTN—nucleus of the optic tract-dorsal terminal nucleus; OPN—olivary pretectal nucleus; POR—postrhinal cortex; PPN—posterior pretectal nucleus; SC—superior colliculus; SCN—suprachiasmatic nucleus; vLGN—ventral lateral geniculate nucleus; vMTN—ventral medial terminal nucleus; V1—primary visual cortex.

Figure 6

Schematic diagram of olfactory outputs indicating projection patterns from the olfactory bulb to the olfactory cortex. The MOB pathways, represented by solid black lines, are divided into parallel pathways originating from TCs and MCs: red arrows indicate the TC pathways; dark blue arrows indicate the MC pathways; and the light blue arrows indicate the AOB pathways. AOB—accessory olfactory bulb; AON—anterior olfactory nucleus; AONd—dorsal part; AONpE—pars external; AONpv—posterior ventral part; APC—anterior piriform cortex; APCd—dorsal part; APCvr—ventrorostral subdivision; HP—hippocampus; LAa—anterior lateral amygdala; Lap—posterior lateral amygdala; LEC—lateral entorhinal cortex; Maa—anterior medial amygdala; Map—posterior medial amygdala; MCs—mitral cells; MOB—main olfactory bulb; MOE—main olfactory epithelium; OT— olfactory tubercle; OTcap—cap part; OTco—cortical part; TCs—tufted cells; TT—tenia tecta; TTd—dorsal part; TTv—ventral part; VNO—vomeronasal organ.

Figure 7

Schematic diagram of altered connections in the AD brain: Red, yellow, and gray lines directed away from the boxes represent efferent fibers which have synaptic contact with each other. The red lines show the altered efferent pathways in AD brain using the neural tracers identified in Table 1. The yellow lines indicate the output pathways that were investigated using various methods, such as electrophysiology, biomedical imaging technologies, and immunohistochemical stanning. The gray dotted lines represent the efferent pathways that affect various symptoms of AD, although the alteration in the connectivity of gray dotted lines has not been directly visualized. A1—primary auditory cortex; AON—anterior olfactory nucleus.