Alzheimer Disease and Selected Risk Factors Disrupt a Co-regulation of Monoamine Oxidase-A/B in the Hippocampus, but Not in the Cortex

Monoamine oxidase-A (MAO-A) and MAO-B have both been implicated in the pathology of Alzheimer disease (AD). We examined 60 autopsied control and AD donor brain samples to determine how well MAO function aligned with two major risk factors for AD, namely sex and APOE ε4 status. MAO-A activity was increased in AD cortical, but not hippocampal, samples. In contrast, MAO-B activity was increased in both regions (with a strong input from female donors) whether sample means were compared based on: (a) diagnosis alone; (b) diagnosis-by-APOE ε4 status (i.e., carriers vs. non-carriers of the ε4 allele); or (c) APOE ε4 status alone (i.e., ignoring ‘diagnosis’ as a variable). Sample means strictly based on the donor’s sex did not reveal any difference in either MAO-A or MAO-B activity. Unexpectedly, we found that cortical MAO-A and MAO-B activities were highly correlated in both males and females (if focussing strictly on the donor’s sex), while in the hippocampus, any correlation was lost in female samples. Stratifying for sex-by-APOE ε4 status revealed a strong correlation between cortical MAO-A and MAO-B activities in both non-carriers and carriers of the allele, but any correlation in hippocampal samples was lost in carriers of the allele. A diagnosis of AD disrupted the correlation between MAO-A and MAO-B activities in the hippocampus, but not the cortex. We observed a novel region-dependent co-regulation of MAO-A and MAO-B mRNAs (but not proteins), while a lack of correlation between MAO activities and the respective proteins corroborated previous reports. Overexpression of human APOE4 increased MAO activity (but not mRNA/protein) in C6 and in HT-22 cell cultures. We identified a novel co-regulation of MAO-A and MAO-B activities that is spared from any influence of risk factors for AD or AD itself in the cortex, but vulnerable to these same factors in the hippocampus. Sex- and region-dependent abilities to buffer influences on brain MAO activities could have significant bearing on ambiguous outcomes when monoaminergic systems are targeted in clinical populations

Still Living Better through Chemistry: An Update on Caloric Restriction and Caloric Restriction Mimetics as Tools to Promote Health and Lifespan

Caloric restriction (CR), the reduction of caloric intake without inducing malnutrition, is the most reproducible method of extending health and lifespan across numerous organisms, including humans. However, with nearly one-third of the world’s population overweight, it is obvious that caloric restriction approaches are difficult for individuals to achieve. Therefore, identifying compounds that mimic CR is desirable to promote longer, healthier lifespans without the rigors of restricting diet. Many compounds, such as rapamycin (and its derivatives), metformin, or other naturally occurring products in our diets (nutraceuticals), induce CR-like states in laboratory models. An alternative to CR is the removal of specific elements (such as individual amino acids) from the diet. Despite our increasing knowledge of the multitude of CR approaches and CR mimetics, the extent to which these strategies overlap mechanistically remains unclear. Here we provide an update of CR and CR mimetic research, summarizing mechanisms by which these strategies influence genome function required to treat age-related pathologies and identify the molecular fountain of youth

Calcium-sensitive regulation of monoamine oxidase-A contributes to the production of peroxyradicals in hippocampal cultures: implications for Alzheimer disease-related pathology

<p>Abstract</p> <p>Background</p> <p>Calcium (Ca²⁺) has recently been shown to selectively increase the activity of monoamine oxidase-A (MAO-A), a mitochondria-bound enzyme that generates peroxyradicals as a natural by-product of the deamination of neurotransmitters such as serotonin. It has also been suggested that increased intracellular free Ca²⁺levels as well as MAO-A may be contributing to the oxidative stress associated with Alzheimer disease (AD).</p> <p>Results</p> <p>Incubation with Ca²⁺selectively increases MAO-A enzymatic activity in protein extracts from mouse hippocampal HT-22 cell cultures. Treatment of HT-22 cultures with the Ca²⁺ionophore A23187 also increases MAO-A activity, whereas overexpression of calbindin-D28K (CB-28K), a Ca²⁺-binding protein in brain that is greatly reduced in AD, decreases MAO-A activity. The effects of A23187 and CB-28K are both independent of any change in MAO-A protein or gene expression. The toxicity (<it>via </it>production of peroxyradicals and/or chromatin condensation) associated with either A23187 or the AD-related β-amyloid peptide, which also increases free intracellular Ca²⁺, is attenuated by MAO-A inhibition in HT-22 cells as well as in primary hippocampal cultures.</p> <p>Conclusion</p> <p>These data suggest that increases in intracellular Ca²⁺availability could contribute to a MAO-A-mediated mechanism with a role in AD-related oxidative stress.</p

PILRalpha, a novel immunoreceptor tyrosine-based inhibitory motif-bearing protein, recruits SHP-1 upon tyrosine phosphorylation and is paired with the truncated counterpart PILRbeta

NRC publication: Ye

PILRα, a Novel Immunoreceptor Tyrosine-based Inhibitory Motif-bearing Protein, Recruits SHP-1 upon Tyrosine Phosphorylation and Is Paired with the Truncated Counterpart PILRβ *

SHP-1-mediated dephosphorylation of protein tyrosine residues is central to the regulation of several cell signaling pathways, the specificity of which is dictated by the intrinsic affinity of SH2 domains for the flanking sequences of phosphotyrosine residues. By using a modified yeast two-hybrid system and SHP-1 as bait, we have cloned a human cDNA, PILRalpha, encoding a 303-amino acid immunoglobulin-like transmembrane receptor bearing two cytoplasmic tyrosines positioned within an immunoreceptor tyrosine-based inhibitory motif. Substrate trapping in combination with pervanadate treatment of 293T cells confirms that PILRalpha associates with SHP-1 in vivo upon tyrosine phosphorylation. Mutation of the tyrosine residues in PILRalpha indicates the pivotal role of the Tyr-269 residue in recruiting SHP-1. Surface plasmon resonance analysis further suggests that the association between PILRalpha-Tyr-269 and SHP-1 is mediated primarily via the amino-terminal SH2 domain of the latter. Polymerase chain reaction amplification of cDNA in combination with genomic sequence analysis revealed a second gene, PILRbeta, coding for a putative activating receptor as suggested by a truncated cytoplasmic tail and a charged lysine residue in its transmembrane region. The PILRalpha and PILRbeta genes are localized to chromosome 7 which is in contrast with the mapping of known members of the inhibitory receptor superfamily

Cannabinoids in the management of behavioral, psychological, and motor symptoms of neurocognitive disorders: a mixed studies systematic review.

AIM: We undertook this systematic review to determine the efficacy and safety of cannabis-based medicine as a treatment for behavioral, psychological, and motor symptoms associated with neurocognitive disorders. METHODS: We conducted a PRISMA-guided systematic review to identify studies using cannabis-based medicine to treat behavioral, psychological, and motor symptoms among individuals with Alzheimer's disease (AD) dementia, Parkinson's disease (PD), and Huntington's disease (HD). We considered English-language articles providing original data on three or more participants, regardless of design. FINDINGS: We identified 25 studies spanning 1991 to 2021 comprised of 14 controlled trials, 5 pilot studies, 5 observational studies, and 1 case series. In most cases, the cannabinoids tested were dronabinol, whole cannabis, and cannabidiol, and the diagnoses included AD (n = 11), PD (n = 11), and HD (n = 3). Primary outcomes were motor symptoms (e.g., dyskinesia), sleep disturbance, cognition, balance, body weight, and the occurrence of treatment-emergent adverse events. CONCLUSIONS: A narrative summary of the findings from the limited number of studies in the area highlights an apparent association between cannabidiol-based products and relief from motor symptoms in HD and PD and an apparent association between synthetic cannabinoids and relief from behavioral and psychological symptoms of dementia across AD, PD, and HD. These preliminary conclusions could guide using plant-based versus synthetic cannabinoids as safe, alternative treatments for managing neuropsychiatric symptoms in neurocognitive vulnerable patient populations

Debate in science: The case of acculturation

The acculturation paradigm of measuring assimilation, separation, integration and marginalization confuses dimensional and categorical conceptions of its constructs, fails to produce ipsative data from mutually exclusive scales, misoperationalizes marginalization as distress, mismeasures biculturalism using double-barreled questions instead of computing it from unicultural measures, and then tends to misinterpret and miscite this faulty science. Extensive published but widely uncited data cast doubt on claims that integration is preferred by minority groups or is beneficial for them. Such salient but unseen problems suggest that the community of acculturation researchers is biased and blinded by an ideology, probably the commendable ideology of liberalism, which advocates freedom of choice, tolerance, plurality, and redress of harm. Phenomenological observations that challenge the paradigm include the absence of studies of majority group acculturation, the well-replicated fact that minorities never prefer pure uniculturalism, the indistinctiveness of cultures, and the predominance of researchers, theory and data from similar Anglo-Saxon settler societies (USA, Australia, Canada)