Mouse model of neurodegeneration: atrophy of basal forebrain cholinergic neurons in trisomy 16 transplants.

Abstract

Vulnerability of specific brain regions and neuronal populations is a characteristic feature of Alzheimer disease and Down syndrome. Cholinergic neurons of the basal forebrain degenerate in both disorders. The basis for neuronal degeneration is unknown. Mouse trisomy 16 (Ts 16) is an animal model of Down syndrome. We sought an experimental system in which the survival and development of Ts 16 basal forebrain cholinergic neurons could be examined beyond the fetal period. As Ts 16 mice do not survive birth, we transplanted fetal Ts 16 and control basal forebrain into the hippocampus of young adult mice. Transplanted neurons survived and grew neurites in all grafts. Over time, we observed selective atrophy of cholinergic neurons in Ts 16 grafts. Denervation of the hippocampus produced a significant increase in the size of Ts 16 cholinergic neurons. This suggests that hippocampal-derived neurotrophic factors acted to prevent degeneration. I3/A4-amyloid-containing plaques were not seen. Ts 16 provides a model of spontaneous, genetically determined neurodegeneration that may be used to understand better the molecular pathogenesis of neuronal dysfunction in Alzheimer disease and Down syndrome.The neuropathological and neurochemical hallmarks of the Alzheimer disease (AD) brain include selective degeneration of certain neuronal populations associated with decreases in their neurotransmitter markers, loss of synapses in the neocortex, accumulation of abnormal fibrillar deposits in neurons (neurofibrillary tangles), and the deposition of amyloidcontaining plaques in the extracellular space (cerebrovascular, diffuse, and neuritic) (1-4). The principal protein component of plaques is a 39-to 42-amino acid amyloid peptide, //A4, which is derived from a larger protein, the amyloid precursor protein (APP) (5-7). The pathogenetic events leading to dementia in AD remain unclear. It is of interest that certain neuronal populations are much more severely affected than others (8). Thus, the early memory loss and intellectual decline in AD may result from the vulnerability and dysfunction of specific populations of neurons.The development of an animal model(s) of AD is critical to understanding the complex neuropathology of the disease. An animal model of Down syndrome (DS)-the trisomy 16 (Ts 16) mouse-may provide a means to study important aspects of the AD phenotype, since 100% of individuals with an extra copy of human chromosome 21 develop AD neuropathology by the fourth decade of life (9-11). Mouse chromosome 16 contains a cluster of genes and loci also located on the long arm of human chromosome 21. These include APP, superoxide dismutase (SOD1), and markers linked to one form of familial AD (12,13). Ts 16 mice demonstrate phenotypic features seen in DS including endocardial cushion defects and hematologic and immunologic abnormalities (10). In addition, the brains of these mice, as in persons with DS, are reduced in size and decreased in cortical thickness (12,14).Basal forebrain cholinergic neurons are vulnerable in ...

In vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model

“…Previous studies have shown that Ts65Dn mice exhibit selective age-dependent atrophy of BFCNs, a progressive decline in numbers of cholinergic neurons in the basal forebrain detected by established cholinergic marker proteins, and astrocytic hypertrophy [18,31,40,41]. The present study combined quantitative MRI and immunocytochemical and enzyme histochemical studies to demonstrate that the loss of cholinergic neurons in Ts65Dn mice is selective for a specific subgroup of cholinergic neurons localized to the MSN and to a lesser degree, the NB.…”

The Novel α7β2-Nicotinic Acetylcholine Receptor Subtype Is Expressed in Mouse and Human Basal Forebrain: Biochemical and Pharmacological Characterization

“…One of the most marked pathologic changes in the brain in Alzheimer disease is the degeneration of this cholinergic projection and the consequent reduction in the number of nAChRs (Dumas and Newhouse, 2011;Pinto et al, 2011). A number of studies have found that the b-amyloid (Ab) peptide (a hallmark of Alzheimer disease) plays a critical role in neuronal degeneration and subsequent memory deficits (Price et al, 1985;Holtzman et al, 1992;Wenk, 1993;Fraser et al, 1997;Capsoni et al, 2000;Dolga et al, 2009). Furthermore, a recent electrophysiological study has demonstrated that Ab binds with higher affinity to a 7 b 2 -nAChR than to a 7 -nAChR, and that this can produce hippocampal neuronal hyperexcitation (through a 7 -nAChR upregulation) and subsequent neurodegeneration (Liu et al, 2013).…”

TrkA expression in the CNS: evidence for the existence of several novel NGF-responsive CNS neurons

“…For trkA expression studies, eight animals were used for in situ hybridization histochemistry (ISHH) and eight for immunocytochemistry. Rats were deeply anesthetized (Holtzman et al, 1992a) and perfused transcardially with 60 ml of PBS (pH 7.4, 4°C) followed by 200 ml of 4% (wt/vol) paraformaldehyde in 0. I M sodium phosphate (pH 7.4, 4°C).…”

“…Sixteen adult female Sprague-Dawley rats were anesthetized (Holtzman et al, 1992a) and brains were removed and placed in cold PBS (pH 7.4, 4°C). The septal region was dissected as described (Johnston et al, 1987).…”