Blood biomarkers for memory: toward early detection of risk for Alzheimer disease, pharmacogenomics, and repurposed drugs.

Short-term memory dysfunction is a key early feature of Alzheimer's disease (AD). Psychiatric patients may be at higher risk for memory dysfunction and subsequent AD due to the negative effects of stress and depression on the brain. We carried out longitudinal within-subject studies in male and female psychiatric patients to discover blood gene expression biomarkers that track short term memory as measured by the retention measure in the Hopkins Verbal Learning Test. These biomarkers were subsequently prioritized with a convergent functional genomics approach using previous evidence in the field implicating them in AD. The top candidate biomarkers were then tested in an independent cohort for ability to predict state short-term memory, and trait future positive neuropsychological testing for cognitive impairment. The best overall evidence was for a series of new, as well as some previously known genes, which are now newly shown to have functional evidence in humans as blood biomarkers: RAB7A, NPC2, TGFB1, GAP43, ARSB, PER1, GUSB, and MAPT. Additional top blood biomarkers include GSK3B, PTGS2, APOE, BACE1, PSEN1, and TREM2, well known genes implicated in AD by previous brain and genetic studies, in humans and animal models, which serve as reassuring de facto positive controls for our whole-genome gene expression discovery approach. Biological pathway analyses implicate LXR/RXR activation, neuroinflammation, atherosclerosis signaling, and amyloid processing. Co-directionality of expression data provide new mechanistic insights that are consistent with a compensatory/scarring scenario for brain pathological changes. A majority of top biomarkers also have evidence for involvement in other psychiatric disorders, particularly stress, providing a molecular basis for clinical co-morbidity and for stress as an early precipitant/risk factor. Some of them are modulated by existing drugs, such as antidepressants, lithium and omega-3 fatty acids. Other drug and nutraceutical leads were identified through bioinformatic drug repurposing analyses (such as pioglitazone, levonorgestrel, salsolidine, ginkgolide A, and icariin). Our work contributes to the overall pathophysiological understanding of memory disorders and AD. It also opens new avenues for precision medicine- diagnostics (assement of risk) as well as early treatment (pharmacogenomically informed, personalized, and preventive).

The "aged garlic extract:" (AGE) and one of its active ingredients S-allyl-L-cysteine (SAC) as potential preventive and therapeutic agents for Alzheimer's disease (AD).

Alzheimer's disease (AD) is the most common form of dementia in the older people and 7(th) leading cause of death in the United States. Deposition of amyloid-beta (Aß) plaques, hyperphosphorylation of microtubule associated protein tau (MAPT), neuroinflammation and cholinergic neuron loss are the major hallmarks of AD. Deposition of Aß peptides, which takes place years before the clinical onset of the disease can trigger hyperphophorylation of tau proteins and neuroinflammation, and the latter is thought to be primarily involved in neuronal and synaptic damage seen in AD. To date, four cholinesterase inhibitors or ChEI (tacrine, rivastigmine, donepezil and galantamine) and a partial NMDA receptor antagonist (memantine) are the only approved treatment options for AD. However, these drugs fail to completely cure the disease, which warrants a search for newer class of targets that would eventually lead to effective drugs for the treatment of AD. In addition to selected pharmacological agents, botanical and medicinal plant extracts are also being investigated. Apart from its culinary use, garlic (Allium sativum) is being used to treat several ailments like cancer and diabetes. Herein we have discussed the effects of a specific 'Aged Garlic Extract' (AGE) and one of its active ingredients, S-allyl-L-cysteine (SAC) in restricting several pathological cascades related to the synaptic degeneration and neuroinflammatory pathways associated with AD. Thus, based on the reported positive preliminary results reviewed herein, further research is required to develop the full potential of AGE and/or SAC into an effective preventative strategy for AD.

Retardation of brain aging by chronic treatment with melatonin.

Slowing the functional decline in the aging brain is not only relevant to nonpathological senescence but also to a broad range of neurodegenerative diseases. Although disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) are not found in the young adult, they gradually manifest with increasing age. AD, in particular, is an increasing major public health concern as the population ages; therapies that delay disease onset will markedly reduce overall disease prevalence. Aging of the brain has been repeatedly associated with cumulative oxidative damage to macromolecules and to abnormal levels of inflammatory activity. Melatonin has attained increasing prominence as a candidate for ameliorating these changes occurring during senescence. Recent research has focused on supplementation with dietary melatonin designed to elucidate the specific key intracellular targets of age-related inflammatory events, and the optimal means of affording protection of these targets. This report summarizes the progress made in this area.

Melatonin affects the metabolism of the beta-amyloid precursor protein in different cell types.

Melatonin is released in mammals during the dark phase of the circadian cycle, and its production declines with age in animals and humans. Since supplemental administration of melatonin may be beneficial in delaying age-related degenerative conditions, it is necessary to study its effect on neuronal differentiation and the processing of key neuronal proteins, such as beta-amyloid precursor protein (beta APP) and synaptophysin. One of the important pathological hallmarks of Alzheimer's disease (AD) is the cerebrovascular deposition of amyloid plaques. The amyloid in senile plaques is mainly composed of the amyloid beta-peptide (A beta) of 39-43 amino acids derived from a larger beta APP. The proteolytic cleavage by 'alpha-secretase' generate soluble derivatives of beta APP (sAPP), lacking the cytoplasmic tail, transmembrane domain, and a small portion of the extracellular domain. Here levels of sAPP and beta APP were analyzed in cell lines of different origins by Western immunoblot of samples from conditioned media and cell lysates, respectively. Normal levels of secretion of sAPP into conditioned media were severely inhibited by treating different cell lines with a high dose of melatonin. In PC12 cells, levels of the fully matured beta APP forms of the post-Golgi compartment were more drastically decreased than the unglycosylated beta APP of the endoplasmic-reticulum (ER) forms. In other cell types, the unglycosylated ER-bound beta APP derivatives are predominant forms that were marginally affected by melatonin treatment. When the treatment of cells with melatonin was withdrawn, the normal level of secretion of sAPP was restored. Melatonin reduces the secretion of soluble A beta. Melatonin also inhibits the secretion of synaptophysin in PC12 cells. Taken together, these data suggest that melatonin probably affects the secretion of sAPP in the conditioned medium by interfering with its full maturation, and melatonin also affects the presysnaptic terminal marker.