Age-related Neurodegenerative Changes Research Articles

Risk factors for exfoliation glaucoma - Current evidence and perspectives.

Exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) represent a complex matrix of ocular age-related neurodegenerative changes. Numerous decades of research on this disease entity have highlighted the unique clinical features of ocular protein-complex aggregates, which lead to tissue dysfunction of the ocular outflow channels, leading to irreversible optic nerve damage and glaucoma. While genetic studies have reported several genes associated with XFS and XFG, numerous studies have shown their association with common systemic diseases such as ischemic heart disease, cerebrovascular accidents, and hypertension. Environmental factors are also reported to play a role in the disease pathogenesis by epigenetic control of gene expression and partly explain the difference in the prevalence rates of the disease process. Despite the identification of possible triggers for the disease onset or for the development of glaucoma, the exact mechanisms or the role of several reported risk factors in disease pathogenesis remain a mystery. This review comprehensively evaluated the several risk factors in XFS and XFG while discussing the interactive interplay between the risk factors that determine the disease onset or phenotype in XFS and XFG.

Mild traumatic brain injury history is associated with lower brain network resilience in soldiers.

Special Operations Forces combat soldiers sustain frequent blast and blunt neurotrauma, most often classified as mild traumatic brain injuries. Exposure to repetitive mild traumatic brain injuries is associated with persistent behavioural, cognitive, emotional and neurological symptoms later in life. Identifying neurophysiological changes associated with mild traumatic brain injury exposure, in the absence of present-day symptoms, is necessary for detecting future neurological risk. Advancements in graph theory and functional MRI have offered novel ways to analyse complex whole-brain network connectivity. Our purpose was to determine how mild traumatic brain injury history, lifetime incidence and recency affected whole-brain graph theoretical outcome measures. Healthy male Special Operations Forces combat soldiers (age = 33.2 ± 4.3 years) underwent multimodal neuroimaging at a biomedical research imaging centre using 3T Siemens Prisma or Biograph MRI scanners in this cross-sectional study. Anatomical and functional scans were preprocessed. The blood-oxygen-level-dependent signal was extracted from each functional MRI time series using the Big Brain 300 atlas. Correlations between atlas regions were calculated and Fisher z-transformed to generate subject-level correlation matrices. The Brain Connectivity Toolbox was used to obtain functional network measures for global efficiency (the average inverse shortest path length), local efficiency (the average global efficiency of each node and its neighbours), and assortativity coefficient (the correlation coefficient between the degrees of all nodes on two opposite ends of a link). General linear models were fit to compare mild traumatic brain injury lifetime incidence and recency. Nonparametric ANOVAs were used for tests on non-normally distributed data. Soldiers with a history of mild traumatic brain injury had significantly lower assortativity than those who did not self-report mild traumatic brain injury (t148 = 2.44, P = 0.016). The assortativity coefficient was significantly predicted by continuous mild traumatic brain injury lifetime incidence [F1,144 = 6.51, P = 0.012]. No differences were observed between recency groups, and no global or local efficiency differences were observed between mild traumatic brain injury history and lifetime incidence groups. Brain networks with greater assortativity have more resilient, interconnected hubs, while those with lower assortativity indicate widely distributed, vulnerable hubs. Greater lifetime mild traumatic brain injury incidence predicted lower assortativity in our study sample. Less resilient brain networks may represent a lack of physiological recovery in mild traumatic brain injury patients, who otherwise demonstrate clinical recovery, more vulnerability to future brain injury and increased risk for accelerated age-related neurodegenerative changes. Future longitudinal studies should investigate whether decreased brain network resilience may be a predictor for long-term neurological dysfunction.

Approach to acute psychosis in older adults.

Approach to acute psychosis in older adults.

Association between walking energy utilisation and longitudinal cognitive performance in older adults.

Human motor function is optimised for energetic efficiency, however, age-related neurodegenerative changes affects neuromotor control of walking. Energy utilisation has been associated with motor performance, but its association with cognitive performance is unknown. The study population included 979 Baltimore Longitudinal Study of Aging participants aged $\ge$50years (52% female, mean age: 70$\pm$10.2years) with a median follow-up time of 4.7years. Energy utilisation for walking was operationalised as a ratio of the energy cost of slow walking to peak walking energy expenditure during standardised tasks ('cost-ratio'). Cognitive functioning was measured using the Trail Making Tests, California Verbal Learning Test, Wechsler Adult Intelligence Scale (WAIS), letter and category fluency and card rotation tests. Linear mixed models adjusted for demographics, education and co-morbidities assessed the association between baseline cost-ratio and cognitive functioning, cross-sectionally and longitudinally. To investigate the relationship among those with less efficient energy utilisation, subgroup analyses were performed. In fully adjusted models, a higher cost-ratio was cross-sectionally associated with poorer performance on all cognitive tests except WAIS (P < 0.05 for all). Among those with compromised energy utilisation, the baseline cost-ratio was also associated with a faster decline in memory (long-delay free recall: β = -0.4, 95% confidence interval [CI] = [-0.8, -0.02]; immediate word recall: β = -1.3, 95% CI = [-2.7, 0.1]). These findings suggest cross-sectional and longitudinal links between energy utilisation and cognitive performance, highlighting an intriguing link between brain function and the energy needed for ambulation. Future research should examine this association earlier in the life course to gauge the potential for interventive mechanisms.

Age-related metabolic and neurodegenerative changes in SAMP8 mice.

The most important risk factor for the development of sporadic Alzheimer’s disease (AD) is ageing. Senescence accelerated mouse prone 8 (SAMP8) is a model of sporadic AD, with senescence accelerated resistant mouse (SAMR1) as a control. In this study, we aimed to determine the onset of senescence-induced neurodegeneration and the related potential therapeutic window using behavioral experiments, immunohistochemistry and western blotting in SAMP8 and SAMR1 mice at 3, 6 and 9 months of age. The Y-maze revealed significantly impaired working spatial memory of SAMP8 mice from the 6th month. With ageing, increasing plasma concentrations of proinflammatory cytokines in SAMP8 mice were detected as well as significantly increased astrocytosis in the cortex and microgliosis in the brainstem. Moreover, from the 3rd month, SAMP8 mice displayed a decreased number of neurons and neurogenesis in the hippocampus. From the 6th month, increased pathological phosphorylation of tau protein at Thr231 and Ser214 was observed in the hippocampi of SAMP8 mice. In conclusion, changes specific for neurodegenerative processes were observed between the 3rd and 6th month of age in SAMP8 mice; thus, potential neuroprotective interventions could be applied between these ages.

Age-related dynamics of morphological changes in the human cortex and corpus callosum: &#x0D; Microgliocytes and neurofilaments as markers of aging

Objectives to analyze the number and sum of diameters of microgliocytes in the precentral gyrus cortex and the corpus callosum of a person in the early adulthood and of an old person and to identify the patterns of neurofilaments expression in these parts of the brain.&#x0D; Material and methods. The results of a sectional study of the cerebral cortex in the precentral gyrus and corpus callosum using hematoxylin and eosin staining were analyzed, and an immunohistochemical study was performed using antibodies to neurofilaments. The dead were divided into two groups depending on their age. The group I included 23 men and 27 women in their early adulthood, aged from 23 to 28 years; the group II included 19 men and 25 women of the old age from 75 to 83 years. We examined the number of microgliocytes, the sum of their diameters, and the expression of neurofilament proteins in the tissue.&#x0D; Results. Morphometric study of autopsy material showed that in the corpus callosum, as well as in the cortex of the precentral gyrus, there was an age-related statistically significant increase in the number of microgliocytes and the sum of their diameters (p 0.001). We found that the expression of neurofilaments in the cortex of the precentral gyrus is uniform both in the early adulthood and in old age. In the corpus callosum tissue, the age-related neurodegenerative changes are more pronounced: by old age, there is a significant decrease in the expression of neurofilaments with the formation of their rarefaction sites in the areas of microgliocyte clusters.&#x0D; Conclusion. The results of morphological study of the precentral gyrus cortex and corpus callosum of two age groups testify that the number and sum of diameters of microgliocytes responsible for the utilization of spent myelin have a certain relationship with age and expression of neurofilaments in the nervous tissue.

TPEN attenuates amyloid-\u03b225\u201335-induced neuronal damage with changes in the electrophysiological properties of voltage-gated sodium and potassium channels

To understand the role of intracellular zinc ion (Zn2+) dysregulation in mediating age-related neurodegenerative changes, particularly neurotoxicity resulting from the generation of excessive neurotoxic amyloid-β (Aβ) peptides, this study aimed to investigate whether N, N, N′, N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a Zn2+-specific chelator, could attenuate Aβ25–35-induced neurotoxicity and the underlying electrophysiological mechanism. We used the 3-(4, 5-dimethyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay to measure the viability of hippocampal neurons and performed single-cell confocal imaging to detect the concentration of Zn2+ in these neurons. Furthermore, we used the whole-cell patch-clamp technique to detect the evoked repetitive action potential (APs), the voltage-gated sodium and potassium (K+) channels of primary hippocampal neurons. The analysis showed that TPEN attenuated Aβ25–35-induced neuronal death, reversed the Aβ25–35-induced increase in intracellular Zn2+ concentration and the frequency of APs, inhibited the increase in the maximum current density of voltage-activated sodium channel currents induced by Aβ25–35, relieved the Aβ25–35-induced decrease in the peak amplitude of transient outward K+ currents (IA) and outward-delayed rectifier K+ currents (IDR) at different membrane potentials, and suppressed the steady-state activation and inactivation curves of IA shifted toward the hyperpolarization direction caused by Aβ25–35. These results suggest that Aβ25–35-induced neuronal damage correlated with Zn2+ dysregulation mediated the electrophysiological changes in the voltage-gated sodium and K+ channels. Moreover, Zn2+-specific chelator-TPEN attenuated Aβ25–35-induced neuronal damage by recovering the intracellular Zn2+ concentration.

Hazelnut Modulates Neurobehaviour and Ameliorates Ageing-induced Oxidative Stress, and Caspase-3-Mediated Apoptosis in Mice.

Organismal aging has been associated with deleterious effects in different body tissues and organs, including the brain. There have been reports from ancient medicinal scripts of the beneficial effects of nuts like hazelnut in preventing aging induced-brain atrophy and memory loss. This study examined the potential beneficial effects of a diet supplemented with two different (Italian and Turkish) cultivars of hazelnut on the brain of aged mice. Aged (24 months old) mice were randomly assigned into 7 groups of ten mice each. Mice were grouped as standard diet (SD) control, three groups of Turkish and three groups of Italian hazelnut incorporated into SD at 2, 4 and 8% respectively. Animals were fed standard or hazelnut diet for 8 weeks. On day 56, behaviours in the elevated plus maze, radial-arm maze, open field, and Y-maze paradigms were monitored and scored, following which animals were euthanized. The brains were removed, weighed and homogenized for the assessment of specific biochemical tests. Results showed that hazelnut-supplemented diet was associated with significantly increased weight gain, with the Italian hazelnut being associated with greater weight gain. The hazelnut- supplemented diet also increased behavioural parameters such as horizontal locomotion and grooming, while it decreased rearing activity. Working-memory also improved significantly with both cultivars of hazelnut, while anxiety indices were reduced at lower concentrations of Italian, and higher concentrations of Turkish hazelnut. Both hazelnut varieties were associated with a reduction in acetylcholinesterase activity, superoxide dismutase activity, nitric oxide levels, caspase- 3 level, but increased dopamine level. Overall, hazelnut cultivars have beneficial effects on the brain in aged mice; suggesting a possible role in the prevention or management of age-related neurodegenerative changes.

Aging Changes Effective Connectivity of Motor Networks During Motor Execution and Motor Imagery.

Age-related neurodegenerative and neurochemical changes are considered to be the basis for the decline of motor function; however, the change of effective connections in cortical motor networks that come with aging remains unclear. Here, we investigated the age-related changes of the dynamic interaction between cortical motor regions. Twenty young subjects and 20 older subjects underwent both right hand motor execution (ME) and right hand motor imagery (MI) tasks by using functional magnetic resonance imaging. Conditional Granger causality analysis (CGCA) was used to compare young and older adults’ effective connectivity among regions of the motor network during the tasks. The more effective connections among motor regions in older adults were found during ME; however, effective within-domain hemisphere connections were reduced, and the blood oxygenation level dependent (BOLD) signal was significantly delayed in older adults during MI. Supplementary motor area (SMA) had a significantly higher In+Out degree within the network during ME and MI in older adults. Our results revealed a dynamic interaction within the motor network altered with aging during ME and MI, which suggested that the interaction with cortical motor neurons caused by the mental task was more difficult with aging. The age-related effects on the motor cortical network provide a new insight into our understanding of neurodegeneration in older individuals.

Absence of age-related neurodegenerative changes during SIV infection and treatment in aged macaques

The advent of combined antiretroviral therapy (CART) has changed HIV infection from a lethal disease to a chronic infection. CART has substantially mitigated infection-associated immunosuppression, related opportunistic infections and HIV encephalitis, nevertheless a substantial percentage of infected individuals are afflicted with a spectrum of HIV-associated neurological disorders (HAND). As approximately 45% of HIV-infected subjects in developed countries are over the age of 50, it has been hypothesized that infection may exacerbate age related neurodegenerative processes. We used the nonhuman primate SIV infection model to test whether chronic infection of aged primates, with or without CART, is associated with accelerated age-related neurodegeneration. Two dozen aged macaques (average age 18 years at entry 20 years at the end) were divided into two groups, half infected with SICmac251 and the other half not. After 10 months, half of each of these groups were either treated or not with CART and followed for an additional 6 months. We previously reported the clinical and neurobehavioural outcome. Here we compared the molecular and histologic findings in the four groups. Using a broad spectrum of histological markers, we found no evidence in the macaques of neuropathological changes associated with aging in humans. While the number of animals is small and length of infection limited, this study does not support the hypothesis that lentiviral infection or treatment accelerates age-related neurodegenerative changes in the primate brain.LEARNING OBJECTIVESThis presentation will enable the learner to:1.Explore current theories on the pathogenesis of lentiviral-related neuropathology2.Explain limitations of nonhuman primate models of age-related human brain changes

Icariin Delays Brain Aging in Senescence-Accelerated Mouse Prone 8 (SAMP8) Model via Inhibiting Autophagy.

Icariin (ICA), a major flavonoid extracted from the Chinese tonic herb Epimedium, exerts beneficial effects in a variety of age-dependent diseases, such as Alzheimer's disease (AD). However, the antiaging mechanisms remain unclear. The senescence-accelerated mouse-prone 8 (SAMP8) model has been used to study age-related neurodegenerative changes associated with aging and the pathogenesis of AD. Hence, the current study was designed to examine the effect of ICA on age-related cognitive decline in SAMP8 mice and explore the role of autophagy in the ICA-mediated neuroprotection. SAMP8 mice were administered with ICA starting at 5 months of age, and the treatment lasted for 3 consecutive months. Morris water maze was used to evaluate cognitive function. The senescence-associated β-galactosidase staining was used to determine the number of senescence cells. The neuronal morphologic changes were examined via Nissl staining. The hippocampal neuronal ultrastructure was examined by transmission electron microscopy. The expression of autophagy protein was examined by Western blot. ICA-treated SAMP8 mice exhibited a robust improvement in spatial learning and memory function. Meanwhile, ICA reduced the number of senescence cells in the brains of SAMP8 mice, inhibited neuronal loss, and reversed neuronal structural changes in the hippocampi of SAMP8 mice. Moreover, ICA treatment also decreased the formation of autophagosomes in the hippocampus of SAMP8 mice, and reduced the expression of autophagy-related proteins LC3-II and p62. These results demonstrate that ICA possesses the ability to delay brain aging in SAMP8 mice, and the mechanisms are possibly mediated through the regulation of autophagy.

Symmetrical and bilateral basal ganglia calcification. Case series and literature review.

Symmetric, bilateral basal ganglia calcification is rare finding that sometimes occurs asymptomatically. Its prevalence increases with age, and the most affected site is the globus pallidus. A series of seven cases with clinical and imaging diagnosis of basal ganglia calcification, recorded during the 2012 to 2016 period at the Department of Internal Medicine of the Hospital Civil de Guadalajara "Fray Antonio Alcalde, is presented. Most common clinical presentation was with altered alertness, headache and seizures. There was one case with movement disorders; there were no cases identified with dementia or tetany. Ganglia calcification can be associated with age-related neurodegenerative changes, but it can be an initial manifestation of a variety of systemic pathologies, including disorders of the calcium metabolism, intoxication by different agents, and autoimmune and genetic diseases. Correlation of typical imaging findings with clinical manifestations and laboratory results should be established to reach a definitive judgment.

Role of mammalian target of rapamycin signaling in autophagy and the neurodegenerative process using a senescence accelerated mouse-prone 8 model.

The mammalian target of rapamycin (mTOR) kinase is an inhibitor of autophagy, which is an intracellular system involved in the degradation of long-lived proteins and organelles in lysosomes. Recent evidence suggests that the steady incline in mTOR function during aging may be associated with the cognitive decline related to aging and may also promote development of Tau pathology. At present, the senescence accelerated mouse prone 8 (SAMP8) is an experimental model that has been proposed for the study of age-related neurodegenerative changes associated with aging. In the present study, mTOR signaling in the hippocampus of SAMP8 newborn mice and in the control-strain SAMR1 mice was investigated. Consequently, hyper phosphorylated Tau (pS199 or pS396) and upregulated mTOR activity were observed in SAMP8 when compared with SAMR1; however, 0.5 µM rapamycin administration significantly reduced the levels of phosphorylated Tau and p70S6K (pT389) in SAMP8 mice. Related to these findings, SAMP8 exhibited an increase in the neuronal loss of hippocampus that was associated with lower levels of anti-apoptotic proteins. These results indicate that mTOR signaling participates in the neurodegenerative process and rapamycin administration may protect neurons of SAMP8 mice and may have a potential role in curing cognitive decline.

AGE-RELATED AND STRESS-INDUCED PROTEINOPATHY OF CEREBRAL NEURONS IN RATS

A study of morphological and functional changes in neurons and glial cells of the cerebral cortex of white rats at the stages of aging and stress-induced neurodegeneration under experiment was investigated. It was found that the age-related neurodegenerative changes in somatosensory cortex neurons of white rats at the age of 30 months are characterized with pronounced signs of proteoinopathy and developing of apoptosis, which is enhanced by exposure to stress factors in clear violation of protein metabolism in the form of accumulation of intra- and extracellular amyloid.

Downregulation of canonical Wnt signaling in hippocampus of SAMP8 mice

In the adult brain, canonical Wnt (Wnt/β-catenin) signaling modulates neuronal function, hippocampal neurogenesis, and synaptic plasticity. Indeed, growing evidence suggests that downregulation of Wnt signaling could be involved in the cognitive decline associated with aging and also with the physiopathology of Alzheimer's disease (AD). However, the molecular basis remains unknown. At present, SAMP8 is an experimental model that has been proposed for studying age-related neurodegenerative changes associated with aging and the pathogenesis of AD. Here, we examined Wnt signaling in the hippocampus of SAMP8 mice at 9 and 12 months of age, as well as in its control-strain SAMR1 mice. Our results showed increased Dickkopf-1 protein levels in SAMP8 with age, in addition to GSK-3 α/β activation and hyperphosphorylated tau. Consequently, higher β-catenin phosphorylation at Ser33,37 and Thr41, which promotes its degradation, along with a decrease in active β-catenin (ABC) in the nucleus, were observed in SAMP8, mainly at the age of 12 months. Moreover, nuclear levels of Dvl3 were lower in 9- and 12-month-old SAMP8 mice. Related to these findings, SAMP8 showed an increase in neuronal loss in the hippocampus that was associated with lower protein levels of the antiapoptotic protein and the Wnt target gene, Bcl-2, in addition to an increase in the proapototic protein Bax. Our results suggest a relationship between age-related downregulation of canonical Wnt signaling and neuronal loss observed in the hippocampus of SAMP8 mice. Thus, enhancing Wnt signaling may represent a novel neuroprotective strategy aimed at counteracting the cognitive decline that is associated not only with aging but also with AD.

How cognitive aging affects multisensory integration of navigational cues

Entorhinal grid cells and hippocampal place cells are key systems for mammalian navigation. By combining information from different sensory modalities, they provide abstract representations of space. Given that both structures are among the earliest to undergo age-related neurodegenerative changes, we asked whether age-related navigational impairments are related to deficient integration of navigational cues. Younger and older adults performed a homing task that required using visual landmarks, self-motion information, or a combination of both. Further, a conflict between cues assessed the influence of each sensory domain. Our findings revealed performance impairments in the older adults, suggestive of a higher noise in the underlying spatial representations. In addition, even though both groups integrated visual and self-motion information to become more accurate and precise, older adults did not place as much influence on visual information as would have been optimal. As these findings were unrelated to potential changes in balance or spatial working memory, this study provides the first evidence that increasing noise and a suboptimal weighting of navigational cues might contribute to the common problems with spatial representations experienced by many older adults. These findings are discussed in the context of the known age-related changes in the entorhinal-hippocampal network.

Neuroprotective effect of Rhodiola rosea Linn against MPTP induced cognitive impairment and oxidative stress.

Ageing and age-related neurodegenerative changes including Parkinson's disease are characterized by an important role of reactive oxygen species. It is characterized by signs of major oxidative stress and mitochondrial damage in the pars compacta of substantia nigra. Present study was designed to investigate whether Rhodiola rosea extract would prevent MPTP induced neurotoxicity in Male wistar rats. Male Wistar rats were divided into following five groups: Group I received vehicle (saline (10 ml/kg for 21 days) orally); Group II received Rhodiola rosea extract (250 mg/kg for 21 days) orally; Group III was treated with 20 mg/kg MPTP i.p. for 21 days; Group IV received 20 mg/kg MPTP, i.p. along with 100 mg/kg Rhodiola rosea orally for 21 days. Group V received 20 mg/kg MPTP i.p. along with 250 mg/kg Rhodiola rosea orally for 21 days. MPTP induced rats showed behavioral alterations in elevated plus maze testing. Group III rats elicited significant increase in lipid hydroperoxide along with reduction in level of glutathione peroxidase, catalase, superoxide dismutase and total antioxidants. Histological evidence revealed that MPTP treated rats shown pathological changes like cellular inflammation and vascular degeneration in brain tissue. The oxidative stress and related biochemical alteration by MPTP were attenuated by Rhodiola rosea treatment. However, further studies may be necessary to elucidate the precise mechanism to support the clinical use of a plant source as antiparkinsonism drug.

Comparative Antioxidant Activities of Soybean and Tempeh Extract in Rat Brain

Soybean and local fermented soybean, tempeh have been known for their health benefits and memory enhancement. It has been reported that soybean has potential role in reducing the progression of neurodegenerative disorder. Reactive oxygen species (ROS) play a crucial role in ageing and age-related neurodegenerative changes. The present study highlighted the comparative studies between total isoflavone extract from soybean and tempeh on the neuronal antioxidant. The total isoflavone extracts were administered orally for 15 days with three selected doses (10, 20 and 40 mg/kg). Piracetam (400 mg/kg, p.o.) was used as standard drug. The measurement of brain catalase, superoxide dismutase (SOD), glutathione (GSH), glutathione reductase (GR), TBARS and nitric oxide (NO) were extended. Our results showed that soybean and tempeh extracts significantly improved antioxidant activities by significantly increased the levels of catalase, SOD, GR and GSH while decreased levels of TBARS and NO level in the rat brain. This suggests that soybean and tempeh extract might be useful in the age-related neurodegenerative changes including management and prevention of Alzheimer’s disease through its antioxidant activities.

Organic bases of late-life depression: a critical update

Late-life depression (LLD) is frequently associated with cognitive impairment and increases the risk of subsequent dementia. Cerebrovascular disease, deep white matter lesions, Alzheimer disease (AD) and dementia with Lewy bodies (DLB) have all been hypothesized to contribute to this increased risk, and a host of studies have looked at the interplay between cerebrovascular disease and LLD. This has resulted in new concepts of LLD, such as "vascular depression", but despite multiple magnetic resonance imaging (MRI) studies in this field, the relationship between structural changes in human brain and LLD is still controversial. While pathological findings of suicide in some elderly persons revealed multiple lacunes, small vessel cerebrovascular disease, AD-related lesions or multiple neurodegenerative pathologies, recent autopsy data challenged the role of subcortical lacunes and white matter lesions as major morphological substrates of depressive symptoms as well as poorer executive function and memory. Several neuropathological studies, including a personal clinico-pathological study in a small cohort of elderly persons with LLD and age-matched controls confirmed that lacunes, periventricular and deep white matter demyelination as well as AD-related lesions are usually unrelated to the occurrence of LLD. In the same line, neuropathological data show that early-onset depression is not associated with an acceleration of age-related neurodegenerative changes. Very recent data on the critical role of glia-modulating neuronal dysfunction and degeneration in depression are discussed.

6. Enhanced recruitment of bone marrow-derived cells into the brain parenchyma in senescence-accelerated mice

Perturbation in the brain–immune interaction may play a role in the pathogenesis of neurodegenerative diseases. The senescence-accelerated mouse prone 10 (SAMP10) mice undergo early onset of age-related neurodegenerative changes and impaired cognition. Given the elevated levels of brain pro-inflammatory cytokines, dystrophic microglia and defects in cytokine-mediated neuroprotective glial responses, as well as an early involution of the thymus and impaired T cell functions, the brain–immune interaction could be perturbed in SAMP10 mice. We created radiation chimeras in which bone marrow cells of young and old SAMP10 and C57BL/6 (B6) mice were reconstituted by bone marrow cells derived from GFP transgenic B6 mice by intra-bone marrow–bone marrow transplantation (IBM–BMT) and analyzed these chimeras 4 months after BMT. In chimeras in which B6 mice were recipients, donor-derived cells entered several discrete regions of the brain parenchyma mostly adjacent to the tenia of the choroid plexus but not the remaining major parts of the brain parenchyma. On the other hand, in chimeras in which old SAMP10 mice were recipients, a larger number of donor-derived cells entered more regions, such as hypothalamus, white matter and brain stem, than in chimeras with B6 mice being recipients. The enhanced recruitment of bone marrow-derived cells into the brain parenchyma in old SAMP10 mice may be a manifestation of disturbances in the brain–immune interaction that might be related to early onset neurodegenerative changes.