Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia. Although previous studies have selectively investigated the localization of amyloid-beta (Aβ) deposition in certain brain regions, a comprehensive characterization of the rostro-caudal distribution of Aβ plaques in the brain and their inter-regional correlation remain unexplored. Our results demonstrated remarkable working and spatial memory deficits in 9-month-old 5xFAD mice compared to wildtype mice. High Aβ plaque load was detected in the somatosensory cortex, piriform cortex, thalamus, and dorsal/ventral hippocampus; moderate levels of Aβ plaques were observed in the motor cortex, orbital cortex, visual cortex, and retrosplenial dysgranular cortex; and low levels of Aβ plaques were located in the amygdala, and the cerebellum; but no Aβ plaques were found in the hypothalamus, raphe nuclei, vestibular nucleus, and cuneate nucleus. Interestingly, the deposition of Aβ plaques was positively associated with brain inter-regions including the prefrontal cortex, somatosensory cortex, medial amygdala, thalamus, and the hippocampus. In conclusion, this study provides a comprehensive morphological profile of Aβ deposition in the brain and its inter-regional correlation. This suggests an association between Aβ plaque deposition and specific brain regions in AD pathogenesis.

Keywords: 5xFAD; Alzheimer’s disease; amyloid-beta (AB); dementia; morphology; neuroanatomy.

FIGURE 1

A symmetrical Y-maze experiment was conducted with Start Arm (S), Familiar Arm (F), Novel Arm (N). 5xFAD mice showed (A) significantly decreased proportion of time spent (%) in the novel arm, (B) significantly decreased frequency of visits to the novel arm, (C) no significant difference in the distance traveled compared to wildtype mice, (D) significantly increased escape latency (s) on days 2, 4, and 7, but no significant differences on days 1, 3, and 6, (E) significant decreased frequency to enter the target quadrant and time spent on the platform in the long-term memory probe test, and (F) no significant difference in the short-term memory probe test.

FIGURE 2

(A,B) Representation of brain rostro-caudal levels of Aβ deposition within the respective coronal brain sections depicted in Figures 2–8. (C) Categorization of Aβ deposition according to the intensity level (0 = no deposition; 1 = mild; 2 = moderate; 3 = high).

FIGURE 3

(A) Coronal section of olfactory-related areas showing Aβ deposition in the granule cell layer of the accessory olfactory bulb (a) and granule cell layer of the olfactory bulb (b). (B) Coronal section of the frontal cortex and olfactory-related areas showing Aβ deposition in the secondary motor cortex (a), prelimbic cortex (b), lateral orbital cortex, ventral orbital cortex (c), medial orbital cortex (d), lateral part of anterior olfactory area (e), and dorsal tenia tecta (f). (C) Coronal section through the cerebral cortex showing Aβ deposition in the primary somatosensory cortex, jaw region of the somatosensory cortex (a), prelimbic cortex (b), caudate putamen, anterior part of anterior commissure (c), infralimbic cortex, dorsal peduncular cortex (d), dorsal tenia tecta, septohippocampal nucleus (e), and nucleus accumbens shell (f).

FIGURE 4

(A) Coronal section through the cerebral cortex showing Aβ deposition in the intermediate part of the lateral septal nucleus (a), area 1 and area 2 of the cingulate cortex (b), primary motor cortex and secondary motor cortex (c), hindlimb region and forelimb region of somatosensory cortex (d), forelimb region and dysgranular zone of somatosensory cortex (e), barrel field of the somatosensory cortex (f), secondary somatosensory cortex (g), ventral part of claustrum and posterior agranular insular cortex (h). (B) Coronal section through the forebrain showing Aβ deposition in CA2 field, CA3 field and dentate gyrus (a), dorsomedial and ventrolateral areas of the laterodorsal thalamic nucleus (b), ventrolateral thalamic nucleus, ventral posterolateral thalamic nucleus (c), ventromedial thalamic nucleus (d), caudate putamen (e), piriform cortex (f), basolateral amygdaloid nucleus (g), anterior part of the basomedial amygdaloid nucleus, and anterior cortical amygdaloid area (h).

FIGURE 5

(A) Coronal section through the forebrain showing Aβ deposition in CA1 field (a), dentate gyrus (b), CA3 field (c), C region of the retrosplenial granular cortex (d), barrel field of the somatosensory cortex, primary somatosensory cortex (e), ectorhinal cortex, perihinal cortex (f), anterior and posterior basolateral amygdaloid nucleus, posterior basomedial amygdaloid nucleus (g), and posterior, ventral posterolateral and ventral posteromedial thalamus (h). (B) Coronal section through the forebrain showing Aβ deposition in the cingulum, pyramidal tract, dorsal fornix and CA1 field (a), dentate gyrus (b), CA2, CA3 (c), primary visual cortex and secondary lateral visual cortex (d), dorsal lateral geniculate nucleus (e), ventral posterolateral and ventral posteromedial thalamus (f), dorsal and ventral part of zona incerta (g), perihinal cortex, and dorsolateral entorhinal cortex (h).

FIGURE 6

(A) Coronal section through the midbrain showing Aβ deposition in the B region and C region of the retrosplenial granular cortex (a), dorsal subiculum (b), primary visual cortex, mediolateral area in the secondary visual cortex (c), primary visual cortex, lateral secondary visual cortex (d), primary auditory cortex, dorsal auditory cortex (e), dorsolateral entorhinal cortex (f), dorsolateral entorhinal cortex (g), and posterior basolateral amygdaloid nucleus (h). (B) Coronal section through the midbrain showing Aβ deposition in the dorsal subiculum (a), dentate gyrus (b), CA3 field and pyramidal tract (c), dorsal and ventral medial geniculate nucleus (d), pyramidal tract, CA3 field, and lacunosum molecular layer of the hippocampus (e), intermediate gray layer of the superior colliculus, intermediate white layer of the superior colliculus (f), anterior pretectal nucleus, p1 reticular formation (g), and lateral and medial mammillary nucleus (h).

FIGURE 7

(A) Coronal section through the midbrain showing Aβ deposition in the retrosplenial dysgranular cortex, A region of retrosplenial granular cortex (a), primary visual cortex (b), lateral secondary visual cortex (c), dorsal hippocampal commissure (d), ectorhinal cortex, perihinal cortex (e), dorsolateral entorhinal cortex (f), caudomedial entorhinal cortex (g), medial lemniscus, longitudinal fasciculus of nucleus, and transverse fibers of the pons (h). (B) Coronal section through the midbrain showing Aβ deposition in the external cortex of the inferior colliculus (a), central nucleus of the inferior colliculus (b), dorsal, ventral, interfascicular, and lateral dorsal raphe (c), ventrolateral periaqueductal gray, laterodorsal tegmental nucleus (d), microcellular tegmental nucleus, lateral lemniscus, intermediate nucleus of the lateral lemniscus (e), oral region of the pontine reticular nucleus (f), reticulotegmental nucleus of the pons (g), supratrigeminal nucleus, peritrigeminal zone, and motor trigeminal nucleus (h).

FIGURE 8

(A) Coronal section through the cerebellum and medulla showing Aβ deposition in lobules 4 and 5 of the cerebellar vermis (a), lobule 3 of the cerebellar vermis (b), lobule 2 of the cerebellar vermis and precentral fissure (c), simple lobule (d), lateral cerebellar nucleus (e), anterior interposed cerebellar nucleus (f), paraflocculus (g), superior vestibular nucleus, and lateral vestibular nucleus (h). (B) Coronal section through the spinal cord showing Aβ deposition in the hypoglossal nucleus (a), medial longitudinal fasciculus (b), ventral medullary reticular nucleus (c), intermediate reticular nucleus (d), dorsal medullary reticular nucleus (e), ambiguus nucleus and rostral ventral respiratory group (f), rubrospinal tract and dorsal medullary reticular nucleus (g), and lateral reticular nucleus (h).

FIGURE 9

(A) Correlation matrix with color scale. A correlation coefficient of 1 represents the maximum positive correlation, whereas, -1 represents the maximum negative correlation. Red indicates 1 and blue indicates -1. (B) A 3D model of the strongest correlated regions. Red represents the somatosensory cortex, orange represents the hippocampus, yellow represents the medial prefrontal cortex, darkgreen represents the ventral posteromedial thalamus, and skyblue represents the medial amygdala, purple presents the posterior thalamus.