Transthyretin and Alzheimer's disease: where in the brain?

Transthyretin (TTR), a carrier protein for thyroxine and retinol in plasma and cerebrospinal fluid (CSF), has been shown to bind the amyloid beta peptide. Accordingly, TTR has been suggested to protect against amyloid beta deposition, a key pathological feature in Alzheimer's disease (AD). Supporting this view are the reduced TTR levels found in CSF of patients with AD, as well as reports of altered TTR expression in the cortex and hippocampus of AD rodent models. Importantly, early characterization of TTR distribution revealed the choroid plexus as the site of TTR synthesis within the brain. To resolve this controversy we used precise laser microdissection technology to assay for TTR mRNA expression. Our results clearly demonstrate that TTR is not produced in the brain parenchyma of wild-type mice nor in two different transgenic mouse models of AD, suggesting that contamination by choroid plexus contributed to the recent results indicating TTR production in various brain regions. The relevance of TTR to AD should now take into consideration TTR production by the choroid plexus and its ability, in the CSF, to sequester the amyloid beta peptide.     

Stereological evaluation of the volume and volume fraction of newborns’ brain compartment and brain in magnetic resonance images

Purpose

Brain development in early life is thought to be critical period in neurodevelopmental disorder. Knowledge relating to this period is currently quite limited. This study aimed to evaluate the volume relation of total brain (TB), cerebrum, cerebellum and bulbus+pons by the use of Archimedes’ principle and stereological (point-counting) method and after that to compare these approaches with each other in newborns.

Methods

This study was carried out on five newborn cadavers mean weighing 2.220?±?1.056?g with no signs of neuropathology. The mean (±SD) age of the subjects was 39.7 (±1.5) weeks. The volume and volume fraction of the total brain, cerebrum, cerebellum and bulbus+pons were determined on magnetic resonance (MR) images using the point-counting approach of stereological methods and by the use of fluid displacement technique.

Results

The mean (±SD) TB, cerebrum, cerebellum and bulbus+pons volumes by fluid displacement were 271.48?±?78.3, 256.6?±?71.8, 12.16?±?6.1 and 2.72?±?1.6?cm³, respectively. By the Cavalieri principle (point-counting) using sagittal MRIs, they were 262.01?±?74.9, 248.11?±?68.03, 11.68?±?6.1 and 2.21?±?1.13?cm³, respectively. The mean (±?SD) volumes by point-counting technique using axial MR images were 288.06?±?88.5, 275.2?±?83.1, 19.75?±?5.3 and 2.11?±?0.7?cm³, respectively. There were no differences between the fluid displacement and point-counting (using axial and sagittal images) for all structures (p?>?0.05).

Conclusion

This study presents the basic data for studies relative to newborn’s brain volume fractions according to two methods. Stereological (point-counting) estimation may be accepted a beneficial and new tool for neurological evaluation in vivo research of the brain. Based on these techniques we introduce here, the clinician may evaluate the growth of the brain in a more efficient and precise manner.     

The blood–brain and the blood–cerebrospinal fluid barriers: function and dysfunction

The central nervous system (CNS) is tightly sealed from the changeable milieu of blood by the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier (BCSFB). While the BBB is considered to be localized at the level of the endothelial cells within CNS microvessels, the BCSFB is established by choroid plexus epithelial cells. The BBB inhibits the free paracellular diffusion of water-soluble molecules by an elaborate network of complex tight junctions (TJs) that interconnects the endothelial cells. Combined with the absence of fenestrae and an extremely low pinocytotic activity, which inhibit transcellular passage of molecules across the barrier, these morphological peculiarities establish the physical permeability barrier of the BBB. In addition, a functional BBB is manifested by a number of permanently active transport mechanisms, specifically expressed by brain capillary endothelial cells that ensure the transport of nutrients into the CNS and exclusion of blood-borne molecules that could be detrimental to the milieu required for neural transmission. Finally, while the endothelial cells constitute the physical and metabolic barrier per se, interactions with adjacent cellular and acellular layers are prerequisites for barrier function. The fully differentiated BBB consists of a complex system comprising the highly specialized endothelial cells and their underlying basement membrane in which a large number of pericytes are embedded, perivascular antigen-presenting cells, and an ensheathment of astrocytic endfeet and associated parenchymal basement membrane. Endothelial cell morphology, biochemistry, and function thus make these brain microvascular endothelial cells unique and distinguishable from all other endothelial cells in the body. Similar to the endothelial barrier, the morphological correlate of the BCSFB is found at the level of unique apical tight junctions between the choroid plexus epithelial cells inhibiting paracellular diffusion of water-soluble molecules across this barrier. Besides its barrier function, choroid plexus epithelial cells have a secretory function and produce the CSF. The barrier and secretory function of the choroid plexus epithelial cells are maintained by the expression of numerous transport systems allowing the directed transport of ions and nutrients into the CSF and the removal of toxic agents out of the CSF. In the event of CNS pathology, barrier characteristics of the blood–CNS barriers are altered, leading to edema formation and recruitment of inflammatory cells into the CNS. In this review we will describe current knowledge on the cellular and molecular basis of the functional and dysfunctional blood–CNS barriers with focus on CNS autoimmune inflammation.     

Permeability of the blood–brain barrier depends on brain temperature

Increased permeability of the blood–brain barrier (BBB) has been reported in different conditions accompanied by hyperthermia, but the role of brain temperature per se in modulating brain barrier functions has not been directly examined. To delineate the contribution of this factor, we examined albumin immunoreactivity in several brain structures (cortex, hippocampus, thalamus and hypothalamus) of pentobarbital-anesthetized rats (50 mg/kg i.p.), which were passively warmed to different levels of brain temperature (32–42 °C). Similar brain structures were also examined for the expression of glial fibrillary acidic protein (GFAP), an index of astrocytic activation, water and ion content, and morphological cell abnormalities. Data were compared with those obtained from drug-free awake rats with normal brain temperatures (36–37 °C). The numbers of albumin- and GFAP-positive cells strongly correlate with brain temperature, gradually increasing from ∼38.5 °C and plateauing at 41–42 °C. Brains maintained at hyperthermia also showed larger content of brain water and Na⁺, K⁺ and Cl⁻ as well as structural abnormalities of brain cells, all suggesting acute brain edema. The latter alterations were seen at ∼39 °C, gradually progressed with temperature increase, and peaked at maximum hyperthermia. Temperature-dependent changes in albumin immunoreactivity tightly correlated with GFAP immunoreactivity, brain water, and numbers of abnormal cells; they were found in each tested area, but showed some structural specificity. Notably, a mild BBB leakage, selective glial activation, and specific cellular abnormalities were also found in the hypothalamus and piriform cortex during extreme hypothermia (32–33 °C); in contrast to hyperthermia these changes were associated with decreased levels of brain water, Na⁺ and K⁺, suggesting acute brain dehydration. Therefore, brain temperature per se is an important factor in regulating BBB permeability, alterations in brain water homeostasis, and subsequent structural abnormalities of brain cells.     

Copulation modifies AR and ERα mRNA expression in the male rat brain

Background/Aims

One day after male sexual behavior [one ejaculation or copulation to satiety (ad libitum copulation during 4 h with the same female)] androgen receptor immunoreactivity (AR-ir) is decreased and estrogen receptor alpha immunoreactivity (ERα-ir) increased in various brain areas related with its control. Seven days after sexual satiety there was a limited recovery of sexual behavior accompanied by a partial recuperation in the AR-ir. In this study we evaluated if these changes in AR-ir and ERα-ir were paralleled by variations in their respective mRNA.

Methods

Sexually experienced male rats were sacrificed at different intervals: immediately, 24 h or seven days after sexual satiety or 24 h after one ejaculation. The changes in AR and ERα mRNA were analyzed by in situ hybridization using digoxigenine-labeled oligonucleotide probes in the MPOA, LSV and the bed nucleus of the stria terminalis, medial division, anterior (BSTMA).

Results

AR mRNA density was decreased in the MPOA and the LSV immediately and 24 h after one ejaculation or sexual satiety. Seven days after copulating to satiety, there was a recovery of AR mRNA. In the BSTMA the different behavioral conditions did not modify the AR mRNA expression. In the MPOA, LSV and BSTMA the ERα mRNA increased after a single ejaculation and at all intervals after sexual satiety.

Conclusion

In some brain areas and after some intervals of sexual activity, the changes in steroid protein receptors expression seem to be consequence of parallel changes in the expression of the respective mRNA.     

Mitochondrial dysfunction: the first domino in brain aging and Alzheimer's disease?

With the increasing average life span of humans and with decreasing cognitive function in elderly individuals, age-related cognitive disorders including dementia have become a major health problem in society. Aging-related mitochondrial dysfunction underlies many common neurodegenerative disorders diseases, including Alzheimer's disease (AD). AD is characterized by two major histopathological hallmarks, initially intracellular and with the progression of the disease extracellular accumulation of oligomeric and fibrillar beta-amyloid (Abeta) peptides and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein. In this review, the authors focus on the latest findings in AD animal models indicating that these histopathological alterations induce deficits in the function of the complexes of the respiratory chain and therefore consecutively result in mitochondrial dysfunction. This parameter is intrinsically tied to oxidative stress. Both are early events in aging and especially in the pathogenesis of aging-related severe neurodegeneration. Ginkgo biloba extract seems to be of therapeutic benefit in the treatment of mild to moderate dementia of different etiology, although the data are quite heterogeneous. Herein, the authors suggest that mitochondrial protection and subsequent reduction of oxidative stress are important components of the neuroprotective activity of Ginkgo biloba extract.     

Do metals that translocate to the brain exacerbate traumatic brain injury?

Metal translocation to the brain is strictly controlled and often prevented by the blood–brain barrier. For the most part, only those metals required to maintain normal function are transported into the brain where they are under tight metabolic control. From the literature, there are reports that traumatic brain injury disrupts the blood–brain barrier. This could allow the influx of metals that would normally have been excluded from the brain. We also have preliminary data showing that metal pellets, surgically-implanted into the leg muscle of a rat to simulate a shrapnel wound, solubilize and the metals comprising the pellet can enter the brain. Surprisingly, rats implanted with a military-grade tungsten alloy composed of tungsten, nickel, and cobalt also showed significantly elevated uranium levels in their brains as early as 1 month after pellet implantation. The only source of uranium was low levels that are naturally found in food and water. Conversely, rats implanted with depleted uranium pellets demonstrated elevated uranium levels in brain resulting from degradation of the implanted pellets. However, when cobalt levels were measured, there were no significant increases in the brain until the rats had reached old age. The only source of cobalt for these rats was the low levels found in their food and water. These data suggest that some metals or metal mixtures (i.e., tungsten alloy), when embedded into muscle, can enhance the translocation of other, endogenous metals (e.g., uranium) across the blood–brain barrier. For other embedded metals (i.e., depleted uranium), this effect is not observed until the animal is of advanced age. This raises the possibility that metal body-burdens can affect blood–brain barrier permeability in a metal-specific and age-dependent manner. This possibility is disconcerting when traumatic brain injury is considered. Traumatic brain injury has been called the “signature” wound of the conflicts in Iraq and Afghanistan, often, an embedded metal fragment wound occurs simultaneously. Since the blood–brain barrier can be disrupted by traumatic brain injury, this raises the possibility of free access to the brain for any metals found in the body. Therefore, we hypothesize that this influx of metals overwhelms normal brain homeostasis, depletes the brain’s antioxidant defense systems, and activates microglial cells resulting in the release of inflammatory mediators that can potentially exacerbate the adverse effects of traumatic brain injury.     

Characterization of the 5′-flanking region and chromosomal assignment of the human brain natriuretic peptide gene

Brain natriuretic peptide (BNP) is a cardiac hormone that occurs predominantly in the ventricle, and synthesis and secretion of BNP are greatly augmented in patients with congestive heart failure and in animal models of ventricular hypertrophy. In order to elucidate the molecular mechanisms underlying the human BNP gene expression in the heart, the human BNP gene was isolated from a size-selected genomic minilibrary. The 1.9-kb human BNP 5-flanking region (–1813 to +110) contained an array of putative cis-acting regulatory elements. Various lengths of the cloned 5-flanking sequences were linked upstream to the bacterial chloramphenicol acetyltransferase (CAT) gene, and their promoter activities were assayed. The 1.9-kb promoter region showed a high-level CAT activity in cultured neonatal rat ventricular cardiocytes. When the CT-rich sequences (–1288 to –1095) were deleted, the high-level activity was reduced to approximately 30%. The 399-bp BNP 5 flanking region (–289 to +110) showed approximately 10% activity of the 1.9-kb region. Furthermore, using human-rodent somatic hybrid cell lines, the BNP gene was assigned to human chromosome 1, on which the atrial natriuretic peptide gene is localized. The present study leads to a better understanding of the molecular mechanisms for the human BNP gene expression in the heart.Abbreviations ANP Atrial natriuretic peptide - AP-1 Activator protein-1 - BNP Brain natriuretic peptide - CAT Chloramphenicol acetyltransferase     

Catecholamines and their metabolites in the brain and urine of rats with experimental Parkinson’s disease

The content of catecholamines and their metabolites in the brain and the relationship between cerebral catecholamine levels and their urinary excretion were studied in rats with 6-OHDA-induced hemiparkinsonism. 6-OHDA reduced brain concentrations of dopamine, DOPAC, and homovanilic acid and urinary excretion of dopamine, dioxyphenilalanine, and DOPAC by more than 90%. A positive correlation was found between the concentrations of these metabolites in the urine and striatum. Measurement of urinary catecholamines and their metabolites is a perspective test for evaluating the status of the dopaminergic nigrosostriate system of the brain in experimental parkinsonism. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 130, No. 8, pp. 223–227, August, 2000     

How well does the CSF inform upon pathology in the brain in Creutzfeldt-Jakob and Alzheimer's diseases?

Analysis of lumbar cerebrospinal fluid (CSF) plays a major role in the investigation of central nervous system disease, but how well do the changes in the CSF reflect pathology within the brain and spinal cord parenchyma? Both Creutzfeldt-Jakob (CJD) and Alzheimer's disease (AD) are characterized by the deposition of insoluble beta-pleated sheet peptides [prion protein (PrP) and beta-amyloid (Abeta), respectively] in the extracellular spaces of grey matter in the brain, but there is discordance in both diseases between the peptide levels in the brain and in the CSF. Experimental studies using tracers have shown that interstitial fluid (ISF) drains through very narrow intercellular spaces within grey matter into bulk flow perivascular channels that surround penetrating arteries. ISF then flows to the surface of the brain and joins CSF to drain to cervical lymph nodes. Such drainage of ISF and CSF to regional lymph nodes in the rat plays a significant role in B-cell and T-cell immune reactions within the brain. In man, the pia mater separates the periarterial ISF drainage pathways from the CSF in the subarachnoid space. The almost complete lack of insoluble protease-resistant PrP entering the CSF from the brain in patients with CJD, reported by Wong et al. in this issue of the Journal of Pathology, illustrates the limitations of ISF drainage pathways for the elimination of insoluble peptides from brain tissue. Insoluble Abeta accumulates in the extracellular spaces as plaques in AD and in periarterial ISF drainage pathways as cerebral amyloid angiopathy. Soluble Abeta appears to become entrapped by the insoluble Abeta in the ISF drainage pathways; thus, as the level of soluble Abeta in the brain rises in AD, the level in the CSF falls. Thus, the changes in the CSF do not accurately reflect the accumulation of the abnormal peptides in the brain parenchyma in either CJD or AD. In both diseases, facilitation of ISF drainage and elimination of PrP and Abeta peptides from the extracellular spaces of the brain may lead to practical therapeutic strategies for these devastating disorders.     

TGFβ signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke

Background  

TGFβ is both neuroprotective and a key immune system modulator and is likely to be an important target for future stroke therapy. The precise function of increased TGF-β1 after stroke is unknown and its pleiotropic nature means that it may convey a neuroprotective signal, orchestrate glial scarring or function as an important immune system regulator. We therefore investigated the time course and cell-specificity of TGFβ signaling after stroke, and whether its signaling pattern is altered by gender and aging.     

How does the brain control lifespan?

There is generally a positive correlation between brain/body size ratio and lifespan, particularly among mammals, suggesting a role for the brain in determining lifespan. Recent studies in diverse organisms including nematodes, flies and rodents have provided evidence that, indeed the brain may control lifespan. Signaling pathways involved in both central nervous system and peripheral stress responses and regulation of energy metabolism may play important roles in lifespan determination. Indeed, genetic and environmental manipulations of these systems can greatly affect lifespan by changing levels of hormones that modulate energy metabolism, stress resistance and regenerative capacity of cells throughout the body. A signal transduction pathway in neurons involving receptors coupled to phosphatidylinositol-3-kinase, Akt and glycogen synthase kinase-3beta appears to play a key role in regulation of longevity by the brain. Mutations in genes that encode proteins in the insulin signaling pathway can increase lifespan in C. elegans and Drosophila, this signaling pathway in neurons in the brain may be particularly important in limiting lifespan. Dietary restriction results in the upregulation of brain-derived neurotrophic factor (BDNF) in the brain, which may increase the resistance of neurons to aging. Interestingly, BDNF signaling in the brain can increase peripheral insulin sensitivity, suggesting a mechanism whereby the brain can control lifespan. We speculate that during evolution the brain took on the task of monitoring and controlling peripheral energy metabolism, and thereby regulating lifespan in the context of food availability. Roles for other evolutionarily conserved brain signaling pathways in lifespan determination are likely to be discovered in the near future.     

Microvesiculation and cell interactions at the brain–endothelial interface in cerebral malaria pathogenesis

Cerebral malaria (CM) is still a major world health problem whose pathogenic mechanisms remain incompletely understood. After reviewing some particularities of anti-malarial immunity, we focus here on the neurovascular aspects of CM. We specifically address the central role of endothelial activation and alteration in disease pathogenesis. We discuss the respective roles of “mediator-induced” versus “host cell-induced” mechanisms of endothelial alteration. The former include cytokines, chemokines and their receptors, while the latter encompass cells located inside and outside the vessel, notably glial cells. We also present evidence for a pathogenic role for membrane microparticles (MP) in CM, based on studies in African patients and in a recognised mouse model. Intervention studies on MP production, via either gene knockout or pharmacological inhibition, can prevent the neurological syndrome and its associated mortality, suggesting potential new therapeutic avenues.     

Are chemokines the third major system in the brain?

Chemokines are a family of small proteins involved in cellular migration and intercellular communication. Although the chemokines and their receptors are located throughout the brain, they are not distributed uniformly. Among the chemokines and their receptors that are arrayed disproportionately in glia and neurons are monocyte chemotactic protein-1/CC chemokine ligand 2 (CCL2), stromal cell-derived factor-1/CXC chemokine ligand 12 (CXCL12), fractalkine/CX3C chemokine ligand 1, interferon-gamma-inducible-protein-10/CXCL10, macrophage inflammatory protein-1alpha/CCL3, and regulated on activation, normal T cell expressed and secreted/CCL5. In the brain, they are found in the hypothalamus, nucleus accumbens, limbic system, hippocampus, thalamus, cortex, and cerebellum. The uneven distribution suggests that there may be functional roles for the chemokine "system," comprised of chemokine ligands and their receptors. In addition to anatomical, immunohistochemical, and in vitro studies establishing the expression of the chemokine ligands and receptors, there is an increasing body of research that suggests that the chemokine system plays a crucial role in brain development and function. Our data indicate that the chemokine system can alter the actions of neuronally active pharmacological agents including the opioids and cannabinoids. Combined with evidence that the chemokine system in the brain interacts with neurotransmitter systems, we propose the following hypothesis: The endogenous chemokine system in the brain acts in concert with the neurotransmitter and neuropeptide systems to govern brain function. The chemokine system can thus be thought of as the third major transmitter system in the brain.     

How does the brain respond to unimodal and bimodal sensory demand in movement of the lower extremity?

Numerous electroencephalography (EEG) studies have shown that neurophysiological signals change in response to visual and sensory adaptations in upper extremity tasks. However, this has not been clearly studied in the lower extremity. In this study, we evaluated how sensory loading affects brain activations related to knee movement. Thirty-two channel EEG was recorded while ten subjects performed knee extension in four different conditions: no weight and no visual target (NWNT), weight affixed to the ankle and no visual target (WNT), no weight and a visual target (NWT), and both weight and target (WT). Surface electromyography (EMG) was recorded from the vastus medialis and vastus lateralis muscles to determine onset of the movement. EEG was epoched from −4.5 s before to 1 s after EMG onset. Epochs were averaged to acquire movement-related cortical potentials (MRCPs) of each task condition. MRCP amplitude during the pre-movement period from −2 s to EMG onset was evaluated at electrodes over motor, sensory, frontal, and parietal areas. The amplitude of the pre-movement potentials for the conditions was different across areas of interest. Over the motor area, NWNT had lower amplitude than any other condition and WT had higher amplitude than any other condition. There was no difference between unimodal NWT and WNT conditions. Mesial frontal and parietal areas showed larger MRCP to the bimodal condition than either unimodal or NWNT conditions. The parietal cortex was the only region that showed a difference between unimodal conditions with greater amplitude for NWT condition. Information concerning added sensory demand is processed by the motor cortex in a way that may be indifferent to the type of modality, but is influenced by the quantity of modalities at the level of the knee. Other brain structures such as parietal and premotor cortices respond based on the modality type to help plan appropriate strategies for motor control in response to sensory manipulations. This suggests that additional task demands in motor training may create a rich sensory environment that may be beneficial in promoting optimal neuromotor recovery.     

The brain’s fingers and hands

The brain keeps track of the changing positions of body parts in space using a spatial body schema. When subjects localise a tactile stimulus on the skin, they might either use a somatotopic body map, or use a body schema to identify the location of the stimulation in external space. Healthy subjects were touched on the fingertips, with the hands in one of two postures: either the right hand was vertically above the left, or the fingers of both hands were interwoven. Subjects made speeded verbal responses to identify either the finger or the hand that was touched. Interweaving the fingers significantly impaired hand identification across several experiments, but had no effect on finger identification. Our results suggest that identification of fingers occurs in a somatotopic representation or finger schema. Identification of hands uses a general body schema, and is influenced by external spatial location. This dissociation implies that touches on the finger can only be identified with a particular hand after a process of assigning fingers to hands. This assignment is based on external spatial location. Our results suggest a role of the body schema in the identification of structural body parts from touch.