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

Abstract

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 (p75NTR) 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 Aβ42 plaque load in DS compared to AD and HC but no differences in APP/Aβ plaque load between HC, AD, and DS. The cerebellar cortex neither displayed Aβ40 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 Aβ42 plaque load. Number of TrkA and p75NTR 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.

Alzheimer's‐like signaling in brains of COVID‐19 patients

“…This finding is in accordance with previous studies showing reduced calbindin expression levels in Purkinje cells and the CA2 hippocampal region of AD patients 37–39 and in cortical pyramidal cells of aged individuals with tau pathology 33,40 . In contrast to the findings in the brains of COVID‐19 patients in the present study, calbindin was not reduced in the cerebellum of AD patients, possibly protecting these cells from AD pathology 39,41 …”

“…33,40 In contrast to the findings in the brains of COVID-19 patients in the present study, calbindin was not reduced in the cerebellum of AD patients, possibly protecting these cells from AD pathology. 39,41 Leaky RyR channels, leading to increased mitochondrial Ca 2+ overload and ROS production and oxidative stress, have been shown…”

Intrathecal amyloid‐beta oligomer administration increases tau phosphorylation in the medial temporal lobe in the African green monkey: A nonhuman primate model of Alzheimer's disease

“…Sections used for this analysis were processed in parallel to avoid batch‐to‐batch differences in chemicals and IHC procedural variables. OD measurements of tau profiles were performed in one field covering an area of 0.40 mm 2 at 40× magnification in the fields of interest (ENT‐O, ENT‐I, CA1, CA2/3, Sub‐C and Sub‐F) displaying strong AT8 immunostaining in an average of 14 sections per case as previously described [42,65]. Background measurements from the corpus callosum were averaged and subtracted from the mean OD values for each immunostained section.…”

Getting Into the Brain: The Intranasal Approach to Enhance the Delivery of Nerve Growth Factor and Its Painless Derivative in Alzheimer’s Disease and Down Syndrome

“…Abnormal levels of the amyloid precursor protein APP found in Ts65Dn mice (Choi et al, 2009) lead to an impaired transport of NGF to BFCNs (Salehi et al, 2006) and the local infusion of NGF rescues the cholinergic deficit in these mice (Cooper et al, 2001). More recently, an increase of the ratio between the precursor of NGF, proNGF, and mature NGF, and imbalance in TrkA/p75 NTR ratio has been found in the brain and plasma from DS patients Miguel et al, 2021). This imbalance is known to trigger neurodegeneration (Capsoni and Cattaneo, 2006;Fahnestock and Shekari, 2019) and to contribute to neuroinflammation (Capsoni et al, 2011;.…”