Dr Dan Johnstone

As human longevity has increased, we have come to understand the ability of the brain to function into advanced age, but also its vulnerability with age, apparent in the age-related dementias. Against that background of success and vulnerability, this essay reviews how the brain is protected by (by our count) 12 mechanisms, including: the cranium, a bony helmet; the hydraulic support given by the cerebrospinal fluid; the strategically located carotid body and sinus, which provide input to reflexes that protect the brain from blood-gas imbalance and extremes of blood pressure; the blood brain barrier, an essential sealing of cerebral vessels; the secretion of molecules such as haemopexin and (we argue) the peptide Aß to detoxify haemoglobin, at sites of a bleed; autoregulation of the capillary bed, which stabilises metabolites in extracellular fluid; fuel storage in the brain, as glycogen; oxygen storage, in the haemoprotein neuroglobin; the generation of new neurones, in the adult, to replace cells lost; acquired resilience, the stress-induced strengthening of cell membranes and energy production found in all body tissues; and cognitive reserve, the ability of the brain to maintain function despite damage. Of these 12 protections, we identify 5 as unique to the brain, 3 as protections shared with all body tissues, and another 4 as protections shared with other tissues but specialised for the brain. These protections are a measure of the brain¿s vulnerability, of its need for protection. They have evolved, we argue, to maintain cognitive function, the ability of the brain to function despite damage that accumulates during life. Several can be tools in the hands of the individual, and of the medical health professional, for the lifelong care of our brains.

Alzheimer's disease, the most common form of dementia, was first formally described in 1907 yet its etiology has remained elusive. Recent proposals that Aß peptide may be part of the brain immune response have revived longstanding contention about the possibility of causal relationships between brain pathogens and Alzheimer's disease. Research has focused on infectious pathogens that may colonize the brain such as herpes simplex type I. Some researchers have proposed the respiratory bacteria Chlamydia pneumoniae may also be implicated in Alzheimer's disease, however this remains controversial. This review aims to provide a balanced overview of the current evidence and its limitations and future approaches that may resolve controversies. We discuss the evidence from in vitro, animal and human studies proposed to implicate Chlamydia pneumoniae in Alzheimer's disease and other neurological conditions, the potential mechanisms by which the bacterium may contribute to pathogenesis and limitations of previous studies that may explain the inconsistencies in the literature.

Pathological forms of the microtubule-associated protein tau are involved in a large group of neurodegenerative diseases named tauopathies, including frontotemporal lobar degeneration (FTLD-tau). K369I mutant tau transgenic mice (K3 mice) recapitulate neural and behavioural symptoms of FTLD, including tau aggregates in the cortex, alterations to nigrostriatum, memory deficits and parkinsonism. The aim of this study was to further characterise the K3 mouse model by examining functional alterations to the striatum. Whole-cell patch-clamp electrophysiology was used to investigate the properties of striatal neurons in K3 mice and wildtype controls. Additionally, striatal-based instrumental learning tasks were conducted to assess goal-directed versus habitual behaviours (i.e., by examining sensitivity to outcome devaluation and progressive ratios). The K3 model demonstrated significant alterations in the discharge properties of striatal neurons relative to wildtype mice, which manifested as a shift in neuronal output towards a burst firing state. K3 mice acquired goal-directed responding faster than control mice and were goal-directed at test unlike wildtype mice, which is likely to indicate reduced capacity to develop habitual behaviour. The observed pattern of behaviour in K3 mice is suggestive of deficits in dorsal lateral striatal function and this was supported by our electrophysiological findings. Thus, both the electrophysiological and behavioural alterations indicate that K3 mice have early deficits in striatal function. This finding adds to the growing literature which indicate that the striatum is impacted in tau-related neuropathies such as FTLD, and further suggests that the K3 model is a unique mouse model for investigating FTLD especially with striatal involvement.

Current treatments for Parkinson's disease (PD) are primarily symptomatic, leaving a need for treatments that mitigate disease progression. One emerging neuroprotective strategy is remote tissue conditioning, in which mild stress in a peripheral tissue (e.g. a limb) induces protection of life-critical organs such as the brain. We evaluated the potential of two remote tissue conditioning interventions ¿ mild ischemia and photobiomodulation ¿ in protecting the brain against the parkinsonian neurotoxin MPTP. Further, we sought to determine whether combining these two interventions provided any added benefit. Male C57BL/6 mice (n = 10/group) were pre-conditioned with either ischemia of the leg (4 × 5 min cycles of ischemia/reperfusion), or irradiation of the dorsum with 670 nm light (50 mW/cm2, 3 min), or both interventions, immediately prior to receiving two MPTP injections 24 hours apart (50 mg/kg total). Mice were sacrificed 6 days later and brains processed for tyrosine hydroxylase immunohistochemistry. Stereological counts of functional dopaminergic neurons in the substantia nigra pars compacta revealed that both remote ischemia and remote photobiomodulation rescued around half of the neurons that were compromised by MPTP (p < 0.001). Combining the two interventions provided no added benefit, rescuing only 40% of vulnerable neurons (p < 0.01). The present results suggest that remote tissue conditioning, whether ischemia of a limb or photobiomodulation of the torso, induces protection of brain centers critical in PD. The lack of additional benefit when combining these two interventions suggests they may share common mechanistic pathways. Further research is needed to identify these pathways and determine the conditioning doses that yield optimal neuroprotection.

The low-density lipoprotein receptor-related protein (LRP) is a large multifunctional cell surface membrane receptor capable of binding over 50 ligands. These include molecules important in Alzheimer's disease such as the amyloid ß-protein precursor (AßPP), the ß-amyloid (Aß) peptide and apolipoprotein E (ApoE). Full length LRP consists of a 515 kDa extracellular ligand binding a-chain and an 85 kDa membrane spanning ß-chain. A soluble form of LRP (sLRP) present in human plasma retains the ability to bind ligands, including Aß. This soluble form is an ectodomain fragment generated from the membrane bound form of the receptor by proteolytic cleavage. Here we report data demonstrating that some commercial 'serum-free' supplements and 'serum-free' media contain unlisted sLRP immunoreactive species that may reflect the presence of undefined serum protein extracts in these 'serum-free' preparations. This has the potential to interfere with experimental results and interpretation in a range of cell culture studies involving LRP or any of its ligands and possibly also other serum proteins.

Aberrant brain iron deposition is observed in both common and rare neurodegenerative disorders, including those categorized as Neurodegeneration with Brain Iron Accumulation (NBIA), which are characterized by focal iron accumulation in the basal ganglia. Two NBIA genes are directly involved in iron metabolism, but whether other NBIA-related genes also regulate iron homeostasis in the human brain, and whether aberrant iron deposition contributes to neurodegenerative processes remains largely unknown. This study aims to expand our understanding of these iron overload diseases and identify relationships between known NBIA genes and their main interacting partners by using a systems biology approach.We used whole-transcriptome gene expression data from human brain samples originating from 101 neuropathologically normal individuals (10 brain regions) to generate weighted gene co-expression networks and cluster the 10 known NBIA genes in an unsupervised manner. We investigated NBIA-enriched networks for relevant cell types and pathways, and whether they are disrupted by iron loading in NBIA diseased tissue and in an in vivo mouse model.We identified two basal ganglia gene co-expression modules significantly enriched for NBIA genes, which resemble neuronal and oligodendrocytic signatures. These NBIA gene networks are enriched for iron-related genes, and implicate synapse and lipid metabolism related pathways. Our data also indicates that these networks are disrupted by excessive brain iron loading.We identified multiple cell types in the origin of NBIA disorders. We also found unforeseen links between NBIA networks and iron-related processes, and demonstrate convergent pathways connecting NBIAs and phenotypically overlapping diseases. Our results are of further relevance for these diseases by providing candidates for new causative genes and possible points for therapeutic intervention.

The 'neurodegeneration with brain iron accumulation' (NBIA) disease family entails movement or cognitive impairment, often with psychiatric features. To understand how iron loading affects the brain, we studied mice with disruption of two iron regulatory genes, hemochromatosis (Hfe) and transferrin receptor 2 (Tfr2). Inductively coupled plasma atomic emission spectroscopy demonstrated increased iron in the Hfe -/- × Tfr2 mut brain (P=0.002, n =5/group), primarily localized by Perls' staining to myelinated structures. Western immunoblotting showed increases of the iron storage protein ferritin light polypeptide and microarray and real-time reverse transcription-PCR revealed decreased transcript levels (P<0.04, n =5/group) for five other NBIA genes, phospholipase A2 group VI, fatty acid 2-hydroxylase, ceruloplasmin, chromosome 19 open reading frame 12 and ATPase type 13A2. Apart from the ferroxidase ceruloplasmin, all are involved in myelin homeostasis; 16 other myelin-related genes also showed reduced expression (P<0.05), although gross myelin structure and integrity appear unaffected (P>0.05). Overlap (P<0.0001) of differentially expressed genes in Hfe -/- × Tfr2 mut brain with human gene co-expression networks suggests iron loading influences expression of NBIA-related and myelin-related genes co-expressed in normal human basal ganglia. There was overlap (P<0.0001) of genes differentially expressed in Hfe -/- × Tfr2 mut brain and post-mortem NBIA basal ganglia. Hfe -/- × Tfr2 mut mice were hyperactive (P<0.0112) without apparent cognitive impairment by IntelliCage testing (P>0.05). These results implicate myelin-related systems involved in NBIA neuropathogenesis in early responses to iron loading. This may contribute to behavioral symptoms in NBIA and hemochromatosis and is relevant to patients with abnormal iron status and psychiatric disorders involving myelin abnormalities or resistant to conventional treatments.