Postnatal Cytoarchitecture and Neurochemical Hippocampal Dysfunction in Down Syndrome.

David G Moreno,Kristian T Schafernak,Nicoleta C Arva,Sylvia E Perez,Elliott J Mufson,Emma C Utagawa

doi:10.3390/jcm10153414

Abstract

Although the prenatal hippocampus displays deficits in cellular proliferation/migration and volume, which are later associated with memory deficits, little is known about the effects of trisomy 21 on postnatal hippocampal cellular development in Down syndrome (DS). We examined postnatal hippocampal neuronal profiles from autopsies of DS and neurotypical (NTD) neonates born at 38-weeks’-gestation up to children 3 years of age using antibodies against non-phosphorylated (SMI-32) and phosphorylated (SMI-34) neurofilament, calbindin D-28k (Calb), calretinin (Calr), parvalbumin (Parv), doublecortin (DCX) and Ki-67, as well as amyloid precursor protein (APP), amyloid beta (Aβ) and phosphorylated tau (p-tau). Although the distribution of SMI-32-immunoreactive (-ir) hippocampal neurons was similar at all ages in both groups, pyramidal cell apical and basal dendrites were intensely stained in NTD cases. A greater reduction in the number of DCX-ir cells was observed in the hippocampal granule cell layer in DS. Although the distribution of Calb-ir neurons was similar between the youngest and oldest NTD and DS cases, Parv-ir was not detected. Conversely, Calr-ir cells and fibers were observed at all ages in DS, while NTD cases displayed mainly Calr-ir fibers. Hippocampal APP/Aβ-ir diffuse-like plaques were seen in DS and NTD. By contrast, no Aβ1–42 or p-tau profiles were observed. These findings suggest that deficits in hippocampal neurogenesis and pyramidal cell maturation and increased Calr immunoreactivity during early postnatal life contribute to cognitive impairment in DS.

Highlights

Down syndrome (DS), a genetic disorder caused by trisomy of chromosome 21 (Ch21), is characterized by substantial developmental delay and intellectual disability during childhood and adulthood [1,2,3,4], which further deteriorate with the age-related onset of amyloid beta (Aβ) plaque and tau bearing neurofibrillary tangle (NFT) pathology similar to that observed in Alzheimer’s disease [5,6,7,8]
Numerous Calr-ir cells and fibers were observed in the youngest DS samples, while Calr-ir fibers only were seen in neurotypically developing (NTD) cases
There were no differences in hippocampal amyloid precursor protein (APP)/Aβ plaque loads between DS and NTD, but p-tau was not detected in any case

Summary

Introduction

Down syndrome (DS), a genetic disorder caused by trisomy of chromosome 21 (Ch21), is characterized by substantial developmental delay and intellectual disability during childhood and adulthood [1,2,3,4], which further deteriorate with the age-related onset of amyloid beta (Aβ) plaque and tau bearing neurofibrillary tangle (NFT) pathology similar to that observed in Alzheimer’s disease [5,6,7,8]. Gestational weeks 10, 15–19, 25, and 34 are crucial periods for the normal development of the human hippocampus which grows steadily from birth to the age of 14 years [15,16]. Studies have found early developmental decreases in hippocampal volume and neuronal density during these critical gestation weeks in individuals with DS [17,18,19]. These decreases have been attributed to impaired neurogenesis during fetal gestation weeks 17–23 [20] due to the overexpression of amyloid precursor protein (APP) and its metabolite Aβ1–42, resulting from trisomy 21 as early as 21 gestational weeks [21]. Giacomini and colleagues [22]

Results

Discussion

Conclusion