New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Spatial memory in aged rats is related to PKCγ-dependent G-protein coupling of the M1 receptor

In the present study, individual differences in spatial memory in aged Fischer 344 (F344) rats were associated with the extent of G-protein coupling of the M1 muscarinic receptor and the dendritic-to-somal ratio of hippocampal PKCγ (d/sPKCγ) immunogenicity. Following testing in the eight-arm radial maze task, 7 young and 13 aged rat brains were sectioned through the dorsal hippocampal formation (HF). G-protein coupling of the M1 receptor was assessed autoradiographically using competition binding studies in the presence and absence of a G-protein uncoupler to determine high ( K H) and low ( K L) affinity states for agonist in the HF, neocortex, and amygdala. In aged animals, a relationship between choice accuracy in the maze and K H, a measure of M1 receptor–G-protein coupling was seen in the dentate gyrus, CA3, CA1, and neocortex. Furthermore, choice accuracy and d/sPKCγ immunogenicity showed a significant relationship in CA1. Lastly, a correlation was seen in the CA1 of aged animals between K H and d/sPKCγ. These relationships did not hold for the amygdala. Thus, individual differences in a naturally occurring age-dependent disruption of cholinergic-PKCγ signal transduction is associated with spatial memory dysfunction

Vesicular Acetylcholine Transporter Density and Alzheimer’s Disease

We have evaluated the vesamicol analogue meta-[ 125I]iodobenzyltrozamicol {(+)-[ 125I]MIBT} as a probe to assess cholinergic terminal integrity in the human temporal cortex. Saturation binding analysis, using 5-aminobenzovesamicol (ABV) to define nonspecific binding, revealed a high-affinity binding site with a K d value of 4.3 ± 1.2 nM in the temporal cortex of the young control subjects. Similar affinity values were observed for (+)-[ 125I]MIBT binding in aged control subjects ( K d = 3.4 ± 0.5 nM) and AD patients ( K d = 3.0 ± 0.8 nM). In contrast, Bmax values for young subjects, aged controls and AD patients were 31.2 ± 6.3, 17.0 ± 2.0 and 9.4 ± 1.6 pmol/g, respectively, clearly reflecting significant reductions in (+)-[ 125I]MIBT binding site density with aging and age-related neuropathology. Moreover, the decrease in (+)-[ 125I]MIBT binding was correlated with choline acetyltransferase activities ( r = 0.72) in the AD temporal cortex. These results suggest that when selective ligands are used, the vesicular acetylcholine transporter can be a useful marker protein for assessing the loss of cholinergic projections in AD and related disorders

Cocaethylene is more potent than cocaine in mediating lethality

Cocaethylene is a pharmacologically active cocaine metabolite that is formed in the presence of ethanol by the activity of liver enzymes. The pharmacology of cocaethylene has not been extensively investigated and its acute toxicity is unknown. The acute toxicity of cocaethylene was compared to cocaine in Swiss-Webster mice. The LD 50 of cocaethylene was 60.7 mg/kg and 63.8 mg/kg in female and male mice, respectively. In comparison, the LD 50 of cocaine was 93.0 mg/kg in both female and male mice. These studies demonstrate that the cocaine-alcohol metabolite, cocathylene, is more potent in mediating lethality than the parent drug

Properties of ibogaine and its principal metabolite (12-hydroxyibogamine) at the MK-801 binding site of the NMDA receptor complex

The putative anti-addiction alkaloid ibogaine and its principal metabolite 12-hydroxyibogamine appear to act at the (+)-5 methyl-10,11-dihydro-5 H-dibenzo[ a,d]cycloheten-5–10-imine maleate (MK-801) binding site in the N-methyl- d-aspartate (NMDA)-receptor cation channel. This conclusion is based on findings that both compounds competitively displaced specific [ 3H]MK-801 binding to membranes from postmortem human caudate and cerebellum and from frog spinal cord. Ibogaine was 4–6 fold more potent than its metabolite and both compounds were less potent (50–1000-fold) than MK-801 binding to the NMDA receptor. In addition, ibogaine (100 μM) and 12-hydroxyibogamine (1 mM) blocked (85–90% of control) the ability of NMDA (100μM, 5 s) to depolarize frog motoneurons in the isolated frog spinal cord. The prevention of NMDA-depolarizations in frog motoneurons showed use-dependency and was very similar to the block produced by MK-801. In view of the abilities of MK-801 to affect the responses to addictive substances in pre-clinical investigations, our results are compatible with the idea that the ability of ibogaine and 12-hydroxyibogamine to interrupt drug-seeking behavior may, in part, result from their actions at the MK-801 binding site

Nature-inspired indolyl-2-azabicyclo[2.2.2]oct-7-ene derivatives as promising agents for the attenuation of withdrawal symptoms: synthesis of 20-desethyl-20-hydroxymethyl-11-demethoxyibogaine

Microwave assisted Diels-Alder cycloaddition of 5-Br-N -benzylpyridinone (2) with methyl acrylate is described to gain an easy access to 7-bromo-2-benzyl-3-oxo-2-aza-5 or 6-carbomethoxy bicyclo[2.2.2]oct-7-enes (3)-(6). The preparation of the ibogaine analogue 20-desethyl-(20-endo)-hydroxymethyl-11-demethoxyibogaine (17) is described by stereoselective hydrogenation of the C(7)-C(8) double bond. Biological evaluation showed an interesting in vitro binding profile toward dopamine transporter, serotonin transporter and opioid receptor systems accompanied by an antiwithdrawal effect in mice for hydroxymethyl 7-indolyl-2-aza-bicyclo[2.2.2]oct-2-ene (14). The simplification of the ibogaine structure appears as a promising approach toward the design of compounds that could reduce the withdrawal symptoms

Overexpression of alpha-synuclein following methamphetamine: is it good or bad?

alpha-Synuclein is a presynaptic protein involved in various degenerative disorders now defined as synucleinopathies. These include neurological diseases that share a few pathological features consisting of aggregates of both normal and altered alpha-synuclein within specific neuronal populations and/or glial cells. The prototype of synucleinopathies is represented by Parkinson's disease (PD) in which alpha-synuclein is identified as a constant component of neuronal pale eosinophilic inclusions: "the Lewy Bodies." In the present article, we discuss the potential significance of amphetamine-induced overexpression of alpha-synuclein in light of clinical findings showing neurodegeneration following overexpression of alpha-synuclein and recent experimental studies that measured increased expression of alpha-synuclein following amphetamine derivatives