Serum MHPG strongly predicts conversion to Alzheimer's disease in behaviorally characterized subjects with Down syndrome.

BACKGROUND: Down syndrome (DS) is the most prevalent genetic cause of intellectual disability. Early-onset Alzheimer's disease (AD) frequently develops in DS and is characterized by progressive memory loss and behavioral and psychological signs and symptoms of dementia (BPSD). Predicting and monitoring the progression of AD in DS is necessary to enable adaptive caretaking. OBJECTIVE: Reliable blood biomarkers that aid the prediction of AD are necessary, since cerebrospinal fluid sampling is rather burdensome, particularly for people with DS. Here, we investigate serum levels of eight biogenic amines and their metabolites in relation to dementia staging and probable BPSD items. METHODS: Using RP-HPLC with electrochemical detection, (nor)adrenergic (NA/A and MHPG), serotonergic (5-HT and 5-HIAA), and dopaminergic (DA, HVA, and DOPAC) compounds were quantified in the serum of DS subjects with established AD at baseline (n = 51), DS subjects without AD (n = 50), non-demented DS individuals that converted to AD over time (n = 50), and, finally, healthy non-DS controls (n = 22). RESULTS: Serum MHPG levels were significantly lower in demented and converted DS subjects (p < 0.0001) compared to non-demented DS individuals and healthy controls. Those subjects with MHPG levels below median had a more than tenfold increased risk of developing dementia. Furthermore, significant correlations were observed between monoaminergic serum values and various probable BPSD items within each DS group. CONCLUSION: Decreased serum MHPG levels show great potential as biomarker to monitor and predict conversion to AD in DS. Moreover, significant monoaminergic alterations related to probable BPSD items, suggesting that monoaminergic dysregulation is an underlying biological mechanism, and demonstrating the need to develop a validated rating scale for BPSD in DS.

LPYFDa neutralizes amyloid-beta-induced memory impairment and toxicity.

Misfolding, oligomerization, and aggregation of the amyloid-beta (Abeta) peptide is widely recognized as a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies have identified soluble Abeta oligomers as the main pathogenic agents and provided evidence that such oligomeric Abeta aggregates are neurotoxic, disrupt synaptic plasticity, and inhibit long-term potentiation. A promising therapeutic strategy in the battle against AD is the application of short synthetic peptides which are designed to bind to specific Abeta-regions thereby neutralizing or interfering with the devastating properties of oligomeric Abeta species. In the present study, we investigated the neuroprotective properties of the amyloid sequence derived pentapeptide LPYFDa in vitro as well as its memory preserving capacity against Abeta(42)-induced learning deficits in vivo. In vitro we showed that neurons in culture treated with LPYFDa are protected against Abeta (42) -induced cell death. Moreover, in vivo LPYFDa prevented memory impairment tested in a contextual fear conditioning paradigm in mice after bilateral intrahippocampal Abeta (42) injections. We thus showed for the first time that an anti-amyloid peptide like LPYFDa can preserve memory by reverting Abeta (42) oligomer-induced learning deficits.