Abnormalities of the nucleus basalis in Down's syndrome

Abstract

One of the most striking manifestations of Down's syndrome is profound mental retardation. Furthermore, after 35 years of age, many patients with Down's syndrome develop clinical and pathological features of Alzheimer's disease. Since brains of patients with Alzheimer's disease show significant loss of neurons in the nucleus basalis of Meynert (nbM), we sought to establish normal standards of nbM neurons in persons with Down's syndrome and to determine whether reductions in the number of neurons occur with increasing age. The number and size of neurons in the nbM were measured in selected sagittal sections from 5 patients with Down's syndrome and 5 age-matched controls. The patients (age range, 16 to 56 years) had 29% fewer nbM neurons than controls, and the oldest patient had the lowest cell count of all subjects. The size of nbM neurons did not differ significantly between the two groups. Our results show that the nbM contains fewer neurons in young persons with Down's syndrome than in normal controls and suggest that the number of these nerve cells may be further reduced in older persons with Down's syndrome.

Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome

“…These reductions are analogous to the loss of forebrain cholinergic neurons seen in both Down syndrome (Casanova et al, 1985;Head et al, 2001;Mann and Esiri, 1989) and Alzheimer's Disease (Candy et al, 1986;Coyle, Price and DeLong, 1983;Vogels et al, 1990;Whitehouse et al, 1985).…”

“…Prior findings indicate that some markers of ACh function in Ts65Dn mice are intact at young ages but emerge in adulthood, generally evident after 6 months of age (Granholm, Sanders and Crnic, 2000). The development of cholinergic dysfunctions in Ts65Dn mice parallels a similar situation in humans with Down syndrome, in whom the basal forebrain cholinergic system appears normal at birth but degenerates in early adulthood (Casanova et al, 1985;Head et al, 2001;Yates et al, 1983). The cholinergic neurons that project to the hippocampus and provide the source of the ACh release measured in the present experiment are located in the medial septum.…”

“…The trisome includes the gene for amyloid precursor protein (Glenner, 1988;Korenberg et al, 1989;Tanzi, 1989), perhaps related to the appearance in individuals with Down syndrome of many neuropathological traits that occur in Alzheimer's Disease. For example, Down syndrome is accompanied by the appearance at about 40 years of age of neuritic plaques, neurofibrillary tangles, and loss of basal forebrain cholinergic neurons (Casanova et al, 1985;Holtzman et al, 1996), pathologies evident also in brain of individuals with Alzheimer's Disease.…”

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

“…In addition, in the present study, an increased density of senescent cells was not only observed in the hippocampus but also in the septum and cingulate cortex of TS +/+/+ mice, and reducing the number of functional copies of Dyrk1A completely rescued this phenotype in these three structures. The septo-hippocampal cholinergic system in learning and attention (Bartus, 2000;Baxter and Chiba, 1999) and this population of neurons undergoes atrophy and degeneration in both AD and aging DS individuals (Mufson et al, 2003;2000;Risser et al, 1997;Casanova et al, 1985;Godridge et al, 1987). In addition, the cingulate cortex and hippocampus, also implicated in learning and AD-related cognitive loss, present the increased accumulation of Aβ oligomers during disease progression (Serrano-Pozo et al, 2011).…”

Comprehensive behavioral assays to enhance phenotype to genotype linkages and therapeutic screening in mouse models of Down syndrome

“…The abnormalities include shorter life expectancies and morphological, neurological, behavioral, structural, and neuronal circuit abnormalities that parallel those in people with DS [8][9][10][11][12][13][14][15]. Furthermore, consistent with the changes demonstrated in imaging and behavioral studies in people with DS [5][6][7], the Ts65Dn model displays deficits in hippocampal structure and function. These changes include deficits in synaptic plasticity, as demonstrated in cellular signaling and electrophysiological studies [8,9,[22][23][24][25][26].…”