Cerebellar Calcium-Binding Protein and Neurotrophin Receptor Defects in Down Syndrome and Alzheimer's Disease

Cerebellar hypoplasia is a major characteristic of the Down syndrome (DS) brain. However, the consequences of trisomy upon cerebellar Purkinje cells (PC) and interneurons in DS are unclear. The present study performed a quantitative and qualitative analysis of cerebellar neurons immunostained with antibodies against calbindin D-28k (Calb), parvalbumin (Parv), and calretinin (Calr), phosphorylated and non-phosphorylated intermediate neurofilaments (SMI-34 and SMI-32), and high (TrkA) and low (p75(NTR)) affinity nerve growth factor (NGF) receptors as well as tau and amyloid in DS (n = 12), Alzheimer's disease (AD) (n = 10), and healthy non-dementia control (HC) (n = 8) cases. Our findings revealed higher A beta(42) plaque load in DS compared to AD and HC but no differences in APP/A beta plaque load between HC, AD, and DS. The cerebellar cortex neither displayed A beta(40) containing plaques nor pathologic phosphorylated tau in any of the cases examined. The number and optical density (OD) measurements of Calb immunoreactive (-ir) PC soma and dendrites were similar between groups, while the number of PCs positive for Parv and SMI-32 were significantly reduced in AD and DS compared to HC. By contrast, the number of SMI-34-ir PC dystrophic axonal swellings, termed torpedoes, was significantly greater in AD compared to DS. No differences in SMI-32- and Parv-ir PC OD measurements were observed between groups. Conversely, total number of Parv- (stellate/basket) and Calr (Lugaro, brush, and Golgi)-positive interneurons were significantly reduced in DS compared to AD and HC. A strong negative correlation was found between counts for Parv-ir interneurons, Calr-ir Golgi and brush cells, and A beta(42) plaque load. Number of TrkA and p75(NTR) positive PCs were reduced in AD compared to HC. These findings suggest that disturbances in calcium binding proteins play a critical role in cerebellar neuronal dysfunction in adults with DS.

Automated summary

The study found that individuals with DS had higher A beta(42) plaque load in cerebellar neurons compared to those with AD and HC. Protein levels and presence of plaques differed between the groups, with AD and DS showing reductions in certain markers. AD had a significantly higher number of dystrophic axonal swellings compared to DS. Additionally, a strong negative correlation was found between the number of certain interneurons and A beta(42) plaque load.