We applied the method for obtaining isogenic cells homozygous for variant B cystatin C, a recessive risk factor for age-related macular degeneration and Alzheimer's disease, in both induced Pluripotent Stem Cells (iPSCs) and a human RPE cell line.
This study identified multiple SNPs in APP and CST3 that were associated with AD at a gene-wise level empirical p-value of 0.05, with odds ratios in the range of 1.5-2.
We will report evidences that the Brain Derived Neurotrophic Factor (BDNF), the most investigated and characterized brain neurotrophin, progranulin, a multi-functional adipokine with trophic and growth factor properties, and cystatin C, a neuroprotective growth factor, are reduced in AD, FTD, and LBD.
Our results may be useful for designing experiments and interpreting results from investigations of manipulation of CysC concentration as an AD therapy.
The positive effect of human cystatin C on the development of Alzheimer's disease has been reported, as it inhibits the formation of β-amyloid oligomers and amyloidogenesis.
The main objective of this study was to determine the prevalence of Cystatin C (CST3), Cathepsin D (CTSD) and Manganese superoxide dismutase (MnSOD) amino acid-altering polymorphisms and their influence on the development of AD in the Ecuadorian population.
Moreover, the over-expression of familial AD-associated presenilin 2 mutations (PS2 M239I and PS2 T122R) resulted in reduced levels of all cystatin C forms (native and glycosylated) and of amyloid-β precursor protein (APP) metabolites within exosomes.
In this study, employing a latex turbidimetric immunoassay, levels of CC in cerebrospinal fluid (CSF) were quantified in 130 age-matched individuals with either a neurological disorder [ALS, Alzheimer's disease (AD), Parkinson's disease (PD), tauopathy (TP), multiple system atrophy (MSA), chronic inflammatory demyelinating polyneuropathy (CIDP)] or no known neurological condition (normal control, NC).
The CST3 BB genotype leads to a reduced secretion of the protein in vitro and increases the risk for AD, suggesting that variability in the CST3 gene and CysC protein concentration may be associated with dementia in Lewy body disease.
Cystatin C, Abeta42, total tau, and phosphorylated tau levels in CSF were analyzed by turbidimetry (cystatin C) and xMAP Luminex technology (Abeta and tau) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28).
Therapeutic manipulation of CysC levels, resulting in slightly higher concentrations than physiological could protect neuronal cells from cell death in AD.
Cathepsin B, Cystatin C, Aβ1-40 and Aβ1-42, total tau, phosphorylated tau, and albumin levels in plasma and CSF were analyzed by ELISA (Cathepsin B) turbidimetry (cystatin C), xMAP Luminex technology (Aβ1-40 and Aβ1-42 and tau), and Cobas C501 analyzer (albumin) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28).
Co-localization of Abeta and cystatin C in the brains of Alzheimer's disease (AD) led to the hypothesis that cystatin C is involved in the disease process.
Most genes conferring susceptibility to AD are related to amyloid-beta deposition (APP; PS1; PS2; APOE; Cystatin-C; ubiquilin-1), oxidative stress (NOS2; NOS3) and inflammatory response (IL-1 alpha; IL-1 beta; IL-6; TNF-alpha).
Thus, cystatin C has a protective role in Alzheimer's disease pathogenesis, and modulation of cystatin C concentrations may have therapeutic implications for the disease.
In conclusion, our data suggest that the CST3 genetic variant is not a susceptibility factor in AD, nor mitigate the effect of the ApoE varepsilon4 allele in the risk of developing AD.
However, cystatin C is also implicated in neuronal degenerative diseases in which it does not form the amyloid protein, such as Alzheimer disease (AD).