Somatomedins in aging and dementia disorders of the Alzheimer type

—Serum levels of somatomedins were determined in apparently healthy aged individuals and dementia patients primarily with clinically suspected Alzheimer type disorder. Serum somatomedin values, determined by radioreceptorassay and radioimmunoassay, fell with advancing age in normal subjects. A significant elevation in serum somatomedins was observed in dementia patients. CSF somatomedin levels were also increased in the only two patients with suspected Alzheimer type disease examined. Since somatomedins are believed to act as anabolic hormones, it was suggested that the elevated levels represent a compensatory mechanism to overcome receptor insensitivity in patients with dementia disorders of the Alzheimer type.     

Increased expression of miRNA-146a in Alzheimer's disease transgenic mouse models

A mouse and human brain-enriched micro-RNA-146a (miRNA-146a) is known to be important in modulating the innate immune response and inflammatory signaling in certain immunological and brain cell types. In this study we examined miRNA-146a levels in early-, moderate- and late-stage Alzheimer's disease (AD) neocortex and hippocampus, in several human primary brain and retinal cell lines, and in 5 different transgenic mouse models of AD including Tg2576, TgCRND8, PSAPP, 3xTg-AD and 5xFAD. Inducible expression of miRNA-146a was found to be significantly up-regulated in a primary co-culture of human neuronal-glial (HNG) cells stressed using interleukin1-beta (IL-1β), and this up-regulation was quenched using specific NF-кB inhibitors including curcumin. Expression of miRNA-146a correlated with senile plaque density and synaptic pathology in Tg2576 and in 5xFAD transgenic mouse models used in the study of this common neurodegenerative disorder.     

Impaired glucose tolerance in midlife and longitudinal changes in brain function during aging

We investigated whether individuals with impaired glucose tolerance (IGT) in midlife subsequently show regionally specific longitudinal changes in regional cerebral blood flow (rCBF) relative to those with normal glucose tolerance (NGT). Sixty-four cognitively normal participants in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging underwent serial ¹⁵O-water positron emission tomography scans (age at first scan, 69.6 ± 7.5 years) and oral glucose tolerance tests 12 years earlier (age at first oral glucose tolerance test, 57.2 ± 11.1 years). Using voxel-based analysis, we compared changes in rCBF over an 8-year period between 15 participants with IGT in midlife and 49 with NGT. Significant differences were observed in longitudinal change in rCBF between the IGT and NGT groups. The predominant pattern was greater rCBF decline in the IGT group in the frontal, parietal, and temporal cortices. Some brain regions in the frontal and temporal cortices also showed greater longitudinal increments in rCBF in the IGT group. Our findings suggest that IGT in midlife is associated with subsequent longitudinal changes in brain function during aging even in cognitively normal older individuals.     

Potential protective effect of honey against chronic cerebral hypoperfusion-induced neurodegeneration in rats

IntroductionTo investigate the neuroprotective potential of Malaysian Tualang honey in chronic cerebral hypoperfusion induced by permanent bilateral common carotid arteries ligation (2VO) in rats.MethodsRats were randomly divided into three groups (n = 10); sham control, honey-untreated 2VO group “2VO” and honey treated 2VO group “2VO + H”. At 10th week of 2VO surgery, all the rat were sacrificed, brains were dissected out, the right hemisphere was processed for histological study, neuronal counts were performed on cresyl violet-stained sections, the number of viable neurons in CA-1 region of the hippocampus were analysed and counted.ResultsThere were damaged, distorted, irregular cells with shrunken cytoplasm and dark pykonotic nuclei in “2VO” rats. Treatment of rats with honey restored the hippocampal cells to their normal structure and reduced loss of neurons in “2VO + H” rats as compared with “2VO” rats.DiscussionThis study shows that Malaysian Tualang honey might have therapeutic potential for the treatment of chronic cerebral hypoperfusion related neurodegenerative disorders.     

Autophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy

Neurodegenerative diseases, such as Alzheimer's disease Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, share a common cellular and molecular pathogenetic mechanism involving aberrant misfolded protein or peptide aggregation and deposition. Autophagy represents a major route for degradation of aggregated cellular proteins and dysfunctional organelles. Emerging studies have demonstrated that up-regulation of autophagy can lead to decreased levels of these toxic aggregate-prone proteins, and is beneficial in the context of aging and various models of neurodegenerative diseases. Understanding the signaling pathways involved in the regulation of autophagy is crucial to the development of strategies for therapy. This review will discuss the cellular and molecular mechanisms of autophagy and its important role in the pathogenesis of aging and neurodegenerative diseases, and the ongoing drug discovery strategies for therapeutic modulation.     

Plaque-bearing mice with reduced levels of oligomeric amyloid-beta assemblies have intact memory function

The amyloid-beta (Abeta) protein exists in the aging mammalian brain in diverse assembly states, including amyloid plaques and soluble Abeta oligomers. Both forms of Abeta have been shown to impair neuronal function, but their precise roles in Alzheimer's disease (AD) -associated memory loss remain unclear. Both types of Abeta are usually present at the same time in the brain, which has made it difficult to evaluate the effects of plaques and oligomers individually on memory function. Recently, a particular oligomeric Abeta assembly, Abeta 56, was found to impair memory function in the absence of amyloid plaques. Until now it has not been possible to determine the effects of plaques, in the absence of Abeta oligomers, on memory function. We have identified Tg2576 mice with plaques but markedly reduced levels of Abeta oligomers, which enabled us to study the effects of plaques alone on memory function. We found that animals with amyloid plaques have normal memory function throughout an episode of reduced Abeta oligomers, which occurs during a period of accelerated amyloid plaque formation. These observations support the importance of Abeta oligomers in memory loss and indicate that, at least initially, amyloid plaques do not impair memory.     

Herpes simplex virus type 1 DNA is present in specific regions of brain from aged people with and without senile dementia of the Alzheimer type.

We have investigated the possible involvement of viruses, specifically Herpes simplex virus type 1, in senile dementia of the Alzheimer type (SDAT). Using the highly sensitive polymerase chain reaction, we have detected the viral thymidine kinase gene in post-mortem brain from 14/21 cases of senile dementia of the Alzheimer type and 9/15 elderly normals. The temporal cortex and hippocampus were usually virus-positive; in contrast, the occipital cortex was virus-negative in 9/9 SDAT cases and 5/5 elderly normals. Temporal and frontal cortex from younger normals (five infants and five middle-aged) were negative. Thus, the presence of Herpes simplex virus type 1 DNA is a region-dependent feature of the aged brain.     

Metallothionein-I and -III expression in animal models of Alzheimer disease

Previous studies have described altered expression of metallothioneins (MTs) in neurodegenerative diseases like multiple sclerosis (MS), Down syndrome, and Alzheimer's disease (AD). In order to gain insight into the possible role of MTs in neurodegenerative processes and especially in human diseases, the use of animal models is a valuable tool. Several transgenic mouse models of AD amyloid deposits are currently available. These models express human beta-amyloid precursor protein (AbetaPP) carrying different mutations that subsequently result in a varied pattern of beta-amyloid (Abeta) deposition within the brain. We have evaluated the expression of MT-I and MT-III mRNA by in situ hybridization in three different transgenic mice models of AD: Tg2576 (carrying AbetaPP harboring the Swedish K670N/M671L mutations), TgCRND8 (Swedish and the Indiana V717F mutations), and Tg-SwDI (Swedish and Dutch/Iowa E693Q/D694N mutations). MT-I mRNA levels were induced in all transgenic lines studied, although the pattern of induction differed between the models. In the Tg2576 mice MT-I was weakly upregulated in cells surrounding Congo Red-positive plaques in the cortex and hippocampus. A more potent induction of MT-I was observed in the cortex and hippocampus of the TgCRND8 mice, likely reflecting their higher amyloid plaques content. MT-I upregulation was also more significant in Tg-SwDI mice, especially in the subiculum and hippocampus CA1 area. Immunofluorescence stainings demonstrate that astrocytes and microglia/macrophages surrounding the plaques express MT-I&II. In general, MT-I regulation follows a similar but less potent response than glial fibrillary acidic protein (GFAP) expression. In contrast to MT-I, MT-III mRNA expression was not significantly altered in any of the models examined suggesting that the various MT isoforms may have different roles in these experimental systems, and perhaps also in human AD.     

A comparative study of choline acetyltransferase from normal and Alzheimer brain

A comparative study was made of the enzyme choline acetyltransferase (ChAT) from normal and Alzheimer (senile dementia of the Alzheimer type) brain. The number of molecular weight and charge forms of the enzyme were determined in the caudate region of both brains. Efficient purification of active ChAT was achieved using immuno-affinity purification. It was shown that the purified enzyme was identical in both cases, exhibiting a single charge (apparent pI approximately 8.2) and a single molecular weight (mol. wt. = 68,000). The idea of a selective loss of one particular isoform to explain the reduced levels of ChAT observed in Alzheimer's disease can be ruled out.     

Philothermal response of polymorphonuclear leukocytes in dementia of the Alzheimer type

—The philothermal response, i.e., the tendency of polymorphonuclear leukocytes (PMNs) to migrate along a temperature gradient toward warmer temperatures, was evaluated in 11 patients with a clinical diagnosis of dementia of the Alzheimer type (DAT) and compared to 11 age and sex-matched mentally normal individuals. While the total number of migrating PMNs did not differ significantly between these two groups, t there was a significant difference in the spatial distribution of the responding cell population. The numerical parameter, R, has been introduced to provide a quantitative measure of the distribution of populations characterized by differences in motile behavior. This R value was unusually high for 10 of the DAT patients but only one of the comparison individuals. No relation between R and duration of illness, age, or sex was detected. These preliminary findings, based on a small number of clinically diagnosed DAT patients, suggest that the philothermal response may represent a biological marker with diagnostic usefulness for at least one subgroup of DAT patients.     

Transient enriched housing before amyloidosis onset sustains cognitive improvement in Tg2576 mice

Levels of educational and occupational attainment, as components of cognitive reserve, may modify the relationship between the pathological hallmarks and cognition in Alzheimer's disease (AD). We examined whether exposure of a Tg2576 transgenic mouse model of AD to environmental enrichment (EE) at a specific period during the amyloidogenic process favored the establishment of a cognitive reserve. We found that exposure to EE during early adulthood of Tg2576 mice—before amyloidogenesis has started—reduced the severity of AD-related cognitive deficits more efficiently than exposure later in life, when the pathology is already present. Interestingly, early-life exposure to EE, while slightly reducing forebrain surface covered by amyloid plaques, did not significantly impact aberrant inhibitory remodeling in the hippocampus of Tg2576 mice. Thus, transient early-life exposure to EE exerts long-lasting protection against cognitive impairment during AD pathology. In addition, these data define the existence of a specific life time frame during which stimulatory activity most efficiently builds a cognitive reserve, limiting AD progression and favoring successful aging.     

Gender differences in apolipoprotein D expression during aging and in Alzheimer disease

Apolipoprotein D (Apo D) is a lipocalin expressed in a wide variety of mammalian tissues. Different studies have shown that this protein is upregulated in the central nervous system (CNS) in several neuropathological conditions, after traumatic brain injury and in aging. The Apo D promoter shows 3 estrogen response elements and it has been shown that its expression is influenced by estrogens in breast cyst fluid. The aim of this work is to study the possible relationship between gender and Apo D expression in human hippocampus and in the entorhinal and frontal cortices during aging and Alzheimer's disease (AD). We visualized Apo D immunohistochemically and then performed a quantification of the chromogen signal strength. Our findings show that Apo D expression is influenced by age, Braak stage, and sex. In most of the studied areas, Apo D expression is increased with age in women but not in men, and in AD progression in both genders. Apo D is always expressed by neurons with no signs of degeneration or death.     

A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer's disease

The postsynaptic density protein PSD-95 is a major element of synapses. PSD-95 is involved in aging, Alzheimer's disease (AD) and numerous psychiatric disorders. However, contradictory data about PSD-95 expression in aging and AD have been reported. Indeed in AD versus control brains PSD-95 varies according to regions, increasing in the frontal cortex, at least in a primary stage, and decreasing in the temporal cortex. In contrast, in transgenic mouse models of aging and AD PSD-95 expression is decreased, in behaviorally aged impaired versus unimpaired rodents it can decrease or increase and finally, it is increased in rodents grown in enriched environments. Different factors explain these contradictory results in both animals and humans, among others concomitant psychiatric endophenotypes, such as depression. The possible involvement of PSD-95 in reactive and/or compensatory mechanisms during AD progression is underscored, at least before the occurrence of important synaptic elimination. Thus, in AD but not in AD transgenic mice, enhanced expression might precede the diminution commonly observed in advanced aging. A two-compartments cell model, separating events taking place in cell bodies and synapses, is presented. Overall these data suggest that AD research will progress by untangling pathological from protective events, a prerequisite for effective therapeutic strategies.     

Apolipoprotein D takes center stage in the stress response of the aging and degenerative brain

Apolipoprotein D (ApoD) is an ancient member of the lipocalin family with a high degree of sequence conservation from insects to mammals. It is not structurally related to other major apolipoproteins and has been known as a small, soluble carrier protein of lipophilic molecules that is mostly expressed in neurons and glial cells within the central and peripheral nervous system. Recent data indicate that ApoD not only supplies cells with lipophilic molecules, but also controls the fate of these ligands by modulating their stability and oxidation status. Of particular interest is the binding of ApoD to arachidonic acid and its derivatives, which play a central role in healthy brain function. ApoD has been shown to act as a catalyst in the reduction of peroxidized eicosanoids and to attenuate lipid peroxidation in the brain. Manipulating its expression level in fruit flies and mice has demonstrated that ApoD has a favorable effect on both stress resistance and life span. The APOD gene is the gene that is upregulated the most in the aging human brain. Furthermore, ApoD levels in the nervous system are elevated in a large number of neurologic disorders including Alzheimer's disease, schizophrenia, and stroke. There is increasing evidence for a prominent neuroprotective role of ApoD because of its antioxidant and anti-inflammatory activity. ApoD emerges as an evolutionarily conserved anti-stress protein that is induced by oxidative stress and inflammation and may prove to be an effective therapeutic agent against a variety of neuropathologies, and even against aging.     

Aging,cortical injury and Alzheimer's disease-like pathology in the guinea pig brain

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized histopathologically by the abnormal deposition of the proteins amyloid-beta (Aβ) and tau. A major issue for AD research is the lack of an animal model that accurately replicates the human disease, thus making it difficult to investigate potential risk factors for AD such as head injury. Furthermore, as age remains the strongest risk factor for most of the AD cases, transgenic models in which mutant human genes are expressed throughout the life span of the animal provide only limited insight into age-related factors in disease development. Guinea pigs (Cavia porcellus) are of interest in AD research because they have a similar Aβ sequence to humans and thus may present a useful non-transgenic animal model of AD. Brains from guinea pigs aged 3–48 months were examined to determine the presence of age-associated AD-like pathology. In addition, fluid percussion-induced brain injury was performed to characterize mechanisms underlying the association between AD risk and head injury. No statistically significant changes were detected in the overall response to aging, although we did observe some region-specific changes. Diffuse deposits of Aβ were found in the hippocampal region of the oldest animals and alterations in amyloid precursor protein processing and tau immunoreactivity were observed with age. Brain injury resulted in a strong and sustained increase in amyloid precursor protein and tau immunoreactivity without Aβ deposition, over 7 days. Guinea pigs may therefore provide a useful model for investigating the influence of environmental and non-genetic risk factors on the pathogenesis of AD.     

PP2A blockade inhibits autophagy and causes intraneuronal accumulation of ubiquitinated proteins

Using cultured cortical neurons, we show that the blockade of protein phosphatase 2A (PP2A), either pharmacologically by okadaic acid or by short hairpin RNA (shRNA)-mediated silencing of PP2A catalytic subunit, inhibited basal autophagy and autophagy induced in several experimental settings (including serum deprivation, endoplasmic reticulum stress, rapamycin, and proteasome inhibition) at early stages before autophagosome maturation. Conversely, PP2A upregulation by PP2A catalytic subunit overexpression stimulates neuronal autophagy. In addition, PP2A blockade resulted in the activation of the negative regulator of autophagy mammalian target of rapamycin complex 1 and 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) and led to intraneuronal accumulation of p62- and ubiquitin-positive protein inclusions, likely due to autophagy downregulation. These data are consistent with previous findings showing that specific invalidation of the autophagy process in the nervous system of mouse resulted in the accumulation of p62- and ubiquitin-positive protein inclusion bodies. Furthermore, we showed that PP2A inhibition alters the distribution of the microtubule-associated protein 1 light chain(LC) 3-I (MAP LC3-I), a key component of the autophagy molecular machinery. Whether MAP LC3-I distribution in the cell accounts for autophagy regulation remains to be determined. These data are important to human neurodegenerative diseases, especially Alzheimer's disease, because they provide links for the first time between the pathological features of Alzheimer's disease:PP2A downregulation, autophagy disruption, and protein aggregation.     

Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) gene interactions with the apolipoprotein E epsilon4 allele as risk factors in Alzheimer's disease and in Parkinson's disease with coexisting Alzheimer pathology

Alzheimer's disease (AD) and Parkinson's disease (PD) are genetically heterogeneous. Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) genes may modify the risk of these disorders. We investigated whether common polymorphisms present in these genes operate as risk factors for AD and PD in Finnish subjects, independently or in concert with the apolipoprotein E ε4 allele (APOE ε4). Eighty late onset sporadic AD patients, 53 PD patients (34 of whom had concomitant AD pathology), and 67 control subjects were genotyped for the insertion (I)/deletion (D) polymorphism of DCP1 and the K variant of BCHE. In logistic regression analysis, the DCP1 *I allele in combination with APOE ε4 significantly increased the risk of AD (OR 30.0, 95% CI 7.3-123.7), compared to subjects carrying neither of the alleles. Similar analysis showed that the risk of AD was significantly increased in subjects carrying both the BCHE wild type (*WT/*WT) genotype and ε4 (OR 9.9, 95% CI 2.9-33.8), compared to those without this BCHE genotype and ε4. Further, the risk of PD with AD pathology was significantly increased for carriers of DCP1 *I and ε4 (OR 8.0, 95% CI 2.1-31.1). We thus conclude that, in Finns, interaction between DCP1 *I and ε4 increases the risk of AD as well as of PD with coexisting Alzheimer pathology, which underlines the importance of the DCP1 I/D polymorphism in the development of Alzheimer neuropathology, whereas the wild type BCHE genotype in combination with ε4 had a combined effect with regard to the risk of AD.


Keywords: Alzheimer's disease; Parkinson's disease; dipeptidyl carboxypeptidase 1; butyrylcholinesterase     

Circular RNAs: emerging players in brain aging and neurodegenerative diseases

Brain aging is closely related to neurodegenerative diseases. Circular RNAs (circRNAs) are a type of conserved RNAs with covalently closed continuous loops. Emerging evidence has shown that circRNAs are implicated in the biology of brain aging and the pathology of age-related neurodegenerative diseases. Here, we summarize current studies on circRNAs associated with brain aging and neurodegenerative diseases by discussing their expression features, pathophysiological roles, and mechanisms of action. We also discuss the potential challenges of circRNA-based therapy against brain aging and neurodegenerative diseases, as well as their potential as diagnostic biomarkers of neurodegenerative diseases. The review provides insights into current progress in the functions of circRNAs in the process of brain aging and neurodegenerative diseases. © 2022 The Pathological Society of Great Britain and Ireland.     

Nerve growth factor and autophagy: effect of nasal anti-NGF-antibodies administration on Ambra1 and Beclin-1 expression in rat brain

Abstract

Nerve growth factor (NGF) exerts protective actions in the healthy and diseased nervous system. Intranasal administration is a suitable and safe strategy to deliver NGF to CNS neurons. We investigated whether nasal anti-NGF-antibody (ANA) administration affects neuronal autophagy, in view of its putative regulatory role in this process. We focused on olfactory bulbs (OB), neocortex (Cx), hippocampus (HF) and septal complex (SC), known to be NGF-responsive and autophagically active. Our combined molecular/morphological results demonstrate that intranasally administered ANA reaches brain NGF-target neurons and lowers the levels of endogenous NGF and its receptors. Treatment also affects – in a brain region-dependent manner – the expression of the autophagic proteins Beclin-1 and Ambra1, as well as that of proteins belonging to the Bcl2 family, namely Bax and Bcl-2, reflecting apoptotic dysregulation. This study provides a nongenetically modified, NGF-defective animal model, representing a suitable tool to investigate novel properties of the neurotrophin, especially in relation to autophagy.     

Lysosomal cathepsins and their regulation in aging and neurodegeneration

Lysosomes and lysosomal hydrolases, including the cathepsins, have been shown to change their properties with aging brain a long time ago, although their function was not really understood. The first biochemical and clinical studies were followed by a major expansion in the last 20 years with the development of animal disease models and new approaches leading to a major advancement of understanding of the role of physiological and degenerative processes in the brain at the molecular level. This includes the understanding of the major role of autophagy and the cathepsins in a number of diseases, including its critical role in the neuronal ceroid lipofuscinosis. Similarly, cathepsins and some other lysosomal proteases were shown to have important roles in processing and/or degradation of several important neuronal proteins, thereby having either neuroprotective or harmful roles. In this review, we discuss lysosomal cathepsins and their regulation with the focus on cysteine cathepsins and their endogenous inhibitors, as well as their role in several neurodegenerative diseases.