CD59 Protects Primary Human Cerebrovascular Smooth Muscle Cells from Cytolytic Membrane Attack Complex.

Cerebral amyloid angiopathy is characterized by a weakening of the small and medium sized cerebral arteries, as their smooth muscle cells are progressively replaced with acellular amyloid ß, increasing vessel fragility and vulnerability to microhemorrhage. In this context, an aberrant overactivation of the complement system would further aggravate this process. The surface protein CD59 protects most cells from complement-induced cytotoxicity, but expression levels can fluctuate due to disease and vary between cell types. The degree to which CD59 protects human cerebral vascular smooth muscle (HCSM) cells from complement-induced cytotoxicity has not yet been determined. To address this shortcoming, we selectively blocked the activity of HCSM-expressed CD59 with an antibody and challenged the cells with complement, then measured cellular viability. Unblocked HCSM cells proved resistant to all tested concentrations of complement, and this resistance decreased progressively with increasing concentrations of anti-CD59 antibody. Complete CD59 blockage, however, did not result in total loss of cellular viability, suggesting that additional factors may have some protective functions. Taken together, this implies that CD59 plays a predominant role in HCSM cellular protection against complement-induced cytotoxicity. Over-expression of CD59 could be an effective means of protecting these cells from excessive complement system activity, with consequent reduction in the incidence of microhemorrhage. The precise extent to which cellular repair mechanisms and other complement repair proteins contribute to this resistance has yet to be fully elucidated.

CD59 Protects Primary Human Cerebrovascular Smooth Muscle Cells from Cytolytic Membrane Attack Complex.

Cerebral amyloid angiopathy is characterized by a weakening of the small- and medium-sized cerebral arteries, as their smooth muscle cells are progressively replaced with acellular amyloid ß, increasing vessel fragility and vulnerability to microhemorrhage. In this context, an aberrant overactivation of the complement system would further aggravate this process. The surface protein CD59 protects most cells from complement-induced cytotoxicity, but expression levels can fluctuate due to disease and varying cell types. The degree to which CD59 protects human cerebral vascular smooth muscle (HCSM) cells from complement-induced cytotoxicity has not yet been determined. To address this shortcoming, we selectively blocked the activity of HCSM-expressed CD59 with an antibody, and challenged the cells with complement, then measured cellular viability. Unblocked HCSM cells proved resistant to all tested concentrations of complement, and this resistance decreased progressively with increasing concentrations of anti-CD59 antibody. Complete CD59 blockage, however, did not result in a total loss of cellular viability, suggesting that additional factors may have some protective functions. Taken together, this implies that CD59 plays a predominant role in HCSM cellular protection against complement-induced cytotoxicity. The overexpression of CD59 could be an effective means of protecting these cells from excessive complement system activity, with consequent reductions in the incidence of microhemorrhage. The precise extent to which cellular repair mechanisms and other complement repair proteins contribute to this resistance has yet to be fully elucidated.

Proteomic analysis of eccrine sweat: implications for the discovery of schizophrenia biomarker proteins.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and multiple reaction monitoring mass spectrometry (MRM-MS) proteomics analyses were performed on eccrine sweat of healthy controls, and the results were compared with those from individuals diagnosed with schizophrenia (SZ). This is the first large scale study of the sweat proteome. First, we performed LC-MS/MS on pooled SZ samples and pooled control samples for global proteomics analysis. Results revealed a high abundance of diverse proteins and peptides in eccrine sweat. Most of the proteins identified from sweat samples were found to be different than the most abundant proteins from serum, which indicates that eccrine sweat is not simply a plasma transudate and may thereby be a source of unique disease-associated biomolecules. A second independent set of patient and control sweat samples were analyzed by LC-MS/MS and spectral counting to determine qualitative protein differential abundances between the control and disease groups. Differential abundances of selected proteins, initially determined by spectral counting, were verified by MRM-MS analyses. Seventeen proteins showed a differential abundance of approximately 2-fold or greater between the SZ pooled sample and the control pooled sample. This study demonstrates the utility of LC-MS/MS and MRM-MS as a viable strategy for the discovery and verification of potential sweat protein disease biomarkers.

Correlation of hypointensities in susceptibility-weighted images to tissue histology in dementia patients with cerebral amyloid angiopathy: a postmortem MRI study.

Neuroimaging with iron-sensitive MR sequences [gradient echo T2* and susceptibility-weighted imaging (SWI)] identifies small signal voids that are suspected brain microbleeds. Though the clinical significance of these lesions remains uncertain, their distribution and prevalence correlates with cerebral amyloid angiopathy (CAA), hypertension, smoking, and cognitive deficits. Investigation of the pathologies that produce signal voids is necessary to properly interpret these imaging findings. We conducted a systematic correlation of SWI-identified hypointensities to tissue pathology in postmortem brains with Alzheimer's disease (AD) and varying degrees of CAA. Autopsied brains from eight AD patients, six of which showed advanced CAA, were imaged at 3T; foci corresponding to hypointensities were identified and studied histologically. A variety of lesions was detected; the most common lesions were acute microhemorrhage, hemosiderin residua of old hemorrhages, and small lacunes ringed by hemosiderin. In lesions where the bleeding vessel could be identified, ß-amyloid immunohistochemistry confirmed the presence of ß-amyloid in the vessel wall. Significant cellular apoptosis was noted in the perifocal region of recent bleeds along with heme oxygenase 1 activity and late complement activation. Acutely extravasated blood and hemosiderin were noted to migrate through enlarged Virchow­Robin spaces propagating an inflammatory reaction along the local microvasculature; a mechanism that may contribute to the formation of lacunar infarcts. Correlation of imaging findings to tissue pathology in our cases indicates that a variety of CAA-related pathologies produce MR-identified signal voids and further supports the use of SWI as a biomarker for this disease.

Imaging cerebral microbleeds using susceptibility weighted imaging: one step toward detecting vascular dementia.

PURPOSE: To monitor changes in the number of cerebral microbleeds (CMBs) in a longitudinal study of healthy controls (HC) and mild-cognitively impaired (MCI) patients using susceptibility weighted imaging (SWI). MATERIALS AND METHODS: SWI was used to image 28 HC and 75 MCI patients annually at 1.5 Tesla over a 4-year period. Magnitude and phase data were used to visualize CMBs for the first and last scans of 103 subjects. RESULTS: Preliminary analysis revealed that none of the 28 HC had more than three CMBs. In the 75 MCI patients, five subjects had more than three CMBs in both first and last scans, while one subject had more than three bleeds only in the last scan. In five of these six MCI patients, the number of CMBs increased over time and all six went on to develop progressive cognitive impairment (PCI). Of the 130 total CMBs seen in the last scans of the six MCI cases, most were less than 4 mm in diameter. CONCLUSION: SWI can reveal small CMBs on the order of 1 mm in diameter and this technique can be used to follow their development longitudinally. Monitoring CMBs may be a means by which to evaluate patients for the presence of microvascular disease that leads to PCI.

Evaluation of a Chitosan Hemostat in a Porcine Laparoscopic Partial Nephrectomy Model: A Pilot Study.

Background and Objective: The ideal hemostatic agent for laparoscopic partial nephrectomy (LPN) would provide complete hemostasis and sealing of the collecting system at a low cost. Chitosan (CS) is an established topical hemostatic agent, but standard sterilization techniques affect its functional and biologic properties, thereby preventing parenteral uses. This study sought to characterize the safety and efficacy of an implanted CS hemostat sterilized with either a standard technique, electron beam (e-beam) irradiation, or a novel technique, nonthermal nitrogen plasma, in a porcine LPN model. Methods: Laparoscopic partial nephrectomies were performed on six farm pigs and hemostasis achieved using only a CS hemostatic agent (Clo-Sur P.A.D.) that was e-beam (n = 3) or plasma sterilized (PS) (n = 3). Number of pads needed to achieve hemostasis, estimated blood loss, operative time, mass of kidney resection, and warm ischemia time were measured. Animals were monitored for 14 weeks and at harvest, retrograde ureteropyelography and histologic analysis were performed. Results: Complete hemostasis and collection system sealing were achieved in both groups. There was a trend toward less pads required for hemostasis (p = 0.056) and reduced blood loss (p = 0.096) with PS pads, although this did not achieve statistical significance. No complications were observed for 14 weeks and gross examination showed the implanted CS was encapsulated in a fibrous capsule. Histologic analysis revealed a healed nephrectomy site with residual CS and associated chronic inflammation, reactive fibrosis, and foreign body giant cell formation. Importantly, the adjacent renal tissue was intact and viable with no residual parenchymal inflammation or cytologic damage. Conclusion: CS pads alone provided safe and effective hemostasis in a porcine LPN model. PS may enhance hemostatic efficacy and resorption compared with e-beam.

Immunophenotypes in the circulation of patients with mild cognitive impairment.

Alterations in the peripheral immune system are associated with dementia and the neuropathology of Alzheimer's disease, but have yet to be studied early in the disease process. To test the hypothesis that the balance of immune cell phenotypes is disrupted in the early progression of memory deterioration, patients with mild cognitive impairment (MCI) and healthy elderly controls were examined for the distribution of subpopulations of leukocytes (lymphocytes, granulocytes, and monocytes) and lymphocyte subtypes (helper/inducer and suppressor/cytotoxic T lymphocytes and B lymphocytes) in blood. MCI subjects had a significantly higher percentage of total lymphocytes and a lower percentage of granulocytes compared to elderly controls. Furthermore, the expression of cell surface amyloid precursor protein (APP) and intracellular amyloid-beta peptide (Abeta) in lymphocytes and monocytes were determined. We found lymphocyte APP expression to be significantly increased in MCI subjects compared to controls. Our data indicate that changes in immunological parameters may be detected early in MCI, and an alteration of the immune response may precede clinical AD.

Longitudinal metabolic and cognitive changes in mild cognitive impairment patients.

Advancements in clinical therapies have identified the need for biomarkers of early Alzheimer disease that distinguish the earliest stages of pathology and target those patients who are likely to gain the most benefit. The aim of this study was to characterize the longitudinal metabolic changes measured by 1H magnetic resonance spectroscopy in correlation to neuropsychologic indices of episodic memory, attention and mental processing speed, language facility, and executive function in subjects with mild cognitive impairment (MCI). Quantitative 1H magnetic resonance spectroscopy of the posterior cingulate gyrus was performed and repeated at 11.56+/-4.3 months. N-acetyl aspartate (NAA), total choline (Cho), total creatine (Cr), myo-inositol (mI), and glutamate/glutamine (Glx) metabolite levels were measured, corrected for cerebrospinal fluid dilution, and ratios calculated in MCI and cognitively normal subjects. In the first study, MCI subjects showed lower NAA levels, NAA/Cho, and NAA/mI ratios and increased Cho/Cr and mI/Cr compared with controls. In the follow-up study, 36% of the MCI subjects [atypical MCI (atMCI)] showed interval increases in NAA, Cr, and Glx levels compared with 64% of MCI subjects (typical MCI) who showed an interval decrease in NAA, Cr, and Glx. Both MCI subgroups had higher Clinical Dementia Rating scores and lower scores on episodic memory, phonemic, and semantic word fluency tasks, compared with controls. The annualized rate of change in metabolic and cognitive status did not differ between normal aging and MCI subjects. atMCI subjects showed significant negative correlations between metabolite levels and executive function task scores, with NAA/mI showing a significant positive correlation with phonemic and semantic word fluency. There were no significant correlations between metabolite levels and cognitive performance in tMCI subjects; however, NAA/mI and mI/Cr were negatively correlated with executive function tasks. These results indicate 2 distinct evolving metabolite profiles that correlate with changes in executive function and can be used to differentiate MCI from normal aging.

Stability and bioactivity of chitosan as a transfection agent in primary human cell cultures: A case for chitosan-only controls.

Chitosan polymers (Cs), from which microparticles (CsM) may be precipitated to deliver various intracellular payloads, are generally considered biologically inert. We examined the impact of cell culture conditions on CsM size and the effect of chitosan on CD59 expression in primary human smooth muscle cells. We found that particle concentration and incubation time in biological buffers augmented particle size. Between pH 7.0 and pH 7.5, CsM size increased abruptly. We utilized CsM containing a plasmid with a gene for CD59 (pCsM) to transfect cells. Both CD59 mRNA and the number of CD59-positive cells were increased after pCsM treatment. Unexpectedly, CsM also augmented the number of CD59-positive cells. Cs alone enhanced CD59 expression more potently than either pCSM or CsM. This observation strongly suggests that chitosan is in fact bioactive and that chitosan-only controls should be included to avoid misattributing the activity of the delivery agent with that of the payload.

Markers of oxidative damage to lipids, nucleic acids and proteins and antioxidant enzymes activities in Alzheimer's disease brain: A meta-analysis in human pathological specimens.

Oxidative stress and decreased cellular responsiveness to oxidative stress are thought to influence brain aging and Alzheimer's disease, but the specific patterns of oxidative damage and the underlying mechanism leading to this damage are not definitively known. The objective of this study was to define the pattern of changes in oxidative-stress related markers by brain region in human Alzheimer's disease and mild cognitive impairment brain tissue. Observational case-control studies were identified from systematic queries of PubMed, ISI Web of Science and Scopus databases and studies were evaluated with appropriate quality measures. The data was used to construct a region-by-region meta-analysis of malondialdehyde, 4-hydroxynonenal, protein carbonylation, 8-hydroxyguanine levels and superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase activities. We also evaluated ascorbic acid, tocopherol, uric acid and glutathione levels. The analysis was complicated in several cases by publication bias and/or outlier data. We found that malondialdehyde levels were slightly increased in the temporal and occipital lobes and hippocampus, but this analysis was significantly impacted by publication bias. 4-hydroxynonenal levels were unchanged in every brain region. There was no change in 8-hydroxyguanine level in any brain region and protein carbonylation levels were unchanged except for a slight increase in the occipital lobe. Superoxide dismutase, glutathione peroxidase and reductase and catalase activities were not decreased in any brain region. There was limited data reporting non-enzymatic antioxidant levels in Alzheimer's disease brain, although glutathione and tocopherol levels appear to be unchanged. Minimal quantitative data is available from brain tissue from patients with mild cognitive impairment. While there is modest evidence supporting minor regional changes in markers of oxidative damage, this analysis fails to identify a consistent pattern of pro-oxidative changes and accumulation of oxidative damage in bulk tissue analysis in the setting of Alzheimer's disease, as has been widely reported.

Regional dissection and determination of loosely bound and non-heme iron in the developing mouse brain.

Iron is a trace metal essential for normal brain development but toxic in excess as it is capable of generating highly reactive radicals that damage cells and tissue. Iron is stringently regulated by the iron regulatory proteins, IRP1 and IRP2, which regulate proteins involved in iron homeostasis at the posttranscriptional level. In this study, 12 distinct regions were microdissected from the mouse brain and regional changes in the levels of loosely bound and non-heme iron that occur with development were measured. We examined 6, 12, and 24 week old wildtype C57BL/6 mice and mice with a targeted deletion of iron regulatory protein 2 (IRP2-/-) that have been reported to develop neurodegenerative symptoms in adulthood. In wildtype mice, levels of loosely bound iron decreased while non-heme iron increased with development. In contrast, an increase in loosely bound and a more pronounced increase in non-heme iron was seen in IRP2-/- mice between 6 and 12 weeks of age, stemming from lower levels at 6 weeks (the youngest age examined) compared to wildtype. These results have implications for understanding the increase in regional brain iron that is associated with normal aging and is postulated to be exacerbated in neurodegenerative disorders.

Iron, copper, and iron regulatory protein 2 in Alzheimer's disease and related dementias.

Accumulating evidence implicates a role for altered iron and copper metabolism in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). However, imbalances in the levels of the various forms of iron at different stages of AD have not been examined. In this pilot study we extracted and measured the levels of loosely bound, non-heme and total iron and copper in the frontal cortex and hippocampus of patients with mild-moderate AD (n=3), severe AD (n=8) and dementia with Lewy bodies (DLB, n=6), using graphite furnace atomic absorption spectrometry (GFAAS). Additionally, the expression of iron regulatory protein 2 (IRP2) was examined in relation to the pathological hallmarks of AD and DLB, amyloid plaques, neurofibrillary tangles (NFT), and Lewy bodies, by immunohistochemistry. We found significantly decreased loosely bound iron in the hippocampal white matter of mild-moderate and severe AD patients and a trend towards increased non-heme iron in the hippocampal gray matter of severe AD patients. Furthermore, decreased levels of total copper were seen in severe AD and DLB frontal cortex compared to controls, suggesting an imbalance in brain metal levels in both AD and DLB. The decrease in loosely bound iron in mild-moderate AD patients may be associated with myelin breakdown seen in the beginning stages of AD and implicates that iron dysregulation is an early event in AD pathogenesis.

Cellular hormetic response to 27-hydroxycholesterol promotes neuroprotection through AICD induction of MAST4 abundance and kinase activity.

The function of the amyloid precursor protein (APP) in brain health remains unclear. This study elucidated a novel cytoprotective signaling pathway initiated by the APP transcriptionally active intracellular domain (AICD) in response to 27-hydroxycholesterol (27OHC), an oxidized cholesterol metabolite associated with neurodegeneration. The cellular response to 27OHC was hormetic, such that low, but not high, doses promoted AICD transactivation of microtubule associated serine/threonine kinase family member 4 (MAST4). MAST4 in turn phosphorylated and inhibited FOXO1-dependent transcriptional repression of rhotekin 2 (RTKN2), an oxysterol stress responder, to optimize cell survival. A palmitate-rich diet, which increases serum 27OHC, or APP ablation, abrogated this response in vivo. Further, this pathway was downregulated in human Alzheimer's Disease (AD) brains but not in frontotemporal dementia brains. These results unveil MAST4 as functional kinase of FOXO1 in a 27OHC AICD-driven, hormetic pathway providing insight for therapeutic approaches against cholesterol associated neuronal disorders.

Preliminary demonstration of an allelic association of the IREB2 gene with Alzheimer's disease.

The role of iron metabolism in Alzheimer's disease (AD) is well documented. Regulation of the proteins that maintain cellular iron metabolism is mediated by two cytoplasmic RNA-binding proteins, the Iron Regulatory Proteins (IRP1 and IRP2), that function through post-transcriptional interactions with RNA stem loop structures called iron-responsive elements. As the primary mediator of iron homeostasis in neuronal cells, IRP2 is a strong candidate for polymorphisms that could impact AD pathogenesis. Thus, we performed a pilot study to assess polymorphisms in the gene encoding IRP2 (IREB2) on clinically well-characterized, post-mortem samples (50 AD and 50 controls). DNA sequence analysis of the IREB2 gene region revealed 14 polymorphisms. Two (rs2656070 and rs13180) showed statistically significant skewing of allelic and genotypic distributions between AD patients and controls. In silico analyses revealed that rs2656070 lies within a probable promoter and disrupts the binding sites of at least two known transcription factors. Though silent and likely not functionally relevant, rs13180 is in complete LD with rs2656070 (D' > 0.999), creating an IREB2-haplotype that is significantly associated with AD. Confirmation of this association in a larger cohort of cases and controls would further support the role of iron regulation in the pathogenesis of this catastrophic and increasingly common neurodegenerative disorder.

Formulation and characterization of a plasma sterilized, pharmaceutical grade chitosan powder.

Chitosan has great potential as a pharmaceutical excipient. In this study, chitosan flake was micronized using cryo-ball and cryo-jet milling and subsequently sterilized with nitrogen plasma. Micronized chitosan was characterized by laser diffraction, scanning electron microscopy (SEM), conductometric titration, viscometry, loss on drying, FTIR, and limulus amebocyte lysate (LAL) assays. Cryo-jet milling produced mean particle size of 16.05µm, 44% smaller than cryo-ball milling. Cryomilled chitosan demonstrated increased hygroscopicity, but reduced molecular weight and degree of deacetylation (DD). SEM imaging showed highly irregular shapes. FTIR showed changes consistent with reduced DD and an unexplained shift at 1100cm(-1). Plasma treated chitosan was sterile with <2.5EU/g after low-pressure plasma and <1.3EU/g after atmospheric pressure plasma treatment. Plasma treatment decreased the reduced viscosity of chitosan flake and powder, with a greater effect on powder. In conclusion, pharmaceutical grade, sterile chitosan powder was produced with cryo-jet milling and plasma sterilization.

Expanding use of nonpenetrating clips in various surgical specialities.

The Anastoclip Vessel Closure System (VCS) (LeMaitre Vascular, Burlington, MA, USA), introduced primarily to facilitate microvascular anastomoses performed during neurosurgical extra-intracranial bypasses, has been used for several other applications as well. The relatively new anastomotic technique includes a clip applier, clip remover, and everting forceps. With the applier, tiny nonpenetrating titanium clips were installed on everted walls of tubular structures. The technical ease of application, reduced anastomotic time, superior hemodynamics, and an improved healing pattern at the anastomosis have been recognized as major advantages compared to conventional suturing. This chapter describes the various indications for use of the system and categorizes them by specific surgical specialties, which include neurosurgery, urology, and gynecology, as well as plastic and reconstructive, vascular, thoracic, transplantation, hepatopancreaticobiliary, and orthopedic and trauma surgery. The largest clinical experience with clips is in vascular access surgery for hemodialysis purposes, both in autologous constructs and with prosthetic grafts. Promising clinical results also have been achieved in neurosurgical cases (both for microvascular anastomoses and with closure of dura mater), microvascular free-tissue transfer, and renal and liver transplantations. Future clinical applications include the use of clips for nerve repair and closure of various types of tubular structures using a laparoscopic approach.

Five years' world experience with nonpenetrating clips for vascular anastomoses.

BACKGROUND: A new sutureless technique has been introduced clinically to facilitate the process of vascular reconstruction and improve patency. The Vessel Closure System (VCS) is nonpenetrating, creates an elastomeric everted anastomosis, and is easily and reproducibly applied. The objective of this report is to review the published world experience that has accrued regarding these clips with attention to the assets, liabilities, and pitfalls associated with the new technology. DATA SOURCES: Medline search and manual cross-referencing were performed, after which 61 original articles were identified on the use of VCS clips for vascular anastomoses. RESULTS: Advantages of the clips compared with sutures include the technical ease of application, the reduced anastomotic time, the superior hemodynamics, and the improved healing pattern of the anastomosis. Disadvantages include the potential problems in atherosclerotic vessels, lack of prospective randomized long-term follow-up, and initial costs. The best clinical results have been achieved in microvascular repair, as well as with vascular access and transplantation surgery. CONCLUSIONS: The VCS clip technology has become an accepted vascular anastomosing technique, which in future could lead to the use of clips as a standard approach and the use of sutures only in case of severe atherosclerosis and other circumstances in which vessel edges are difficult to evert.

Evolution of staples and clips for vascular anastomoses.

Because of the development of less invasive surgical techniques, there is an increasing demand for vascular anastomosing techniques that require less exposure of the operating field. This paper reviews the most important representatives of staples, clips, and other mechanical devices for vascular anastomosing described over the last five decades. This report is organized in three parts: (1) the history of clipping and stapling devices, (2) development of the Vessel Closure System (VCS) clips, and (3) current and potential status of mechanical vascular anastomotic devices. A Medline literature search was conducted and publications on the use of staples and/or clips for the creation of vascular anastomoses identified with extensive cross-referencing. The first literature description of a mechanical vascular stapling device was by Gudov in 1950. This and other reports from the Soviet Union stimulated brisk, competitive development of vascular anastomotic devices in Europe, North America, and Japan. Fasteners included staples, penetrating pin-rings, or toothed stainless steel clips, none of which gained acceptance because of their complexity and inability to facilitate end-to-side anastomoses. A more convenient and less traumatic anastomotic system (VCS Clip applier system) was introduced into clinical practice in 1995. This system differs from staples in that it is non-penetrating. A wide variety of reports have described the advantages, both technical and biological, that clips provide over conventional needle-and-suture, particularly for the construction of vascular access for hemodialysis. A steady evolution of mechanical vascular anastomotic devices has sought to eliminate the technical and biological disadvantages of conventional suturing. Although the conventional hand-sewn, overcast non-absorbable suture remains the "gold" standard, newer techniques such as the non-penetrating arcuate-legged VCS clips are gaining acceptance as a useful addition to the vascular surgeons' armamentarium.

From development to dysfunction: microglia and the complement cascade in CNS homeostasis.

Of the many mysteries that surround the brain, few surpass the awe-inspiring complexity of its development. The intricate wiring of the brain at both the system and molecular level is both spatially and temporally regulated in perfect synchrony. How such a delicate, yet elegant, system arises from an embryo's most basic cells remains at the forefront of neuroscientific research. At the cellular level, the competitive dance between synapses struggling to gain dominance seems to be refereed by both neurons themselves and microglia, the innate immune cells of the nervous system. Additionally, the unexpected complement cascade, a major effecter arm of the innate immune system, is almost certainly involved in synaptic remodeling by tagging destined neurons and synapses for destruction. As suddenly as they appear, the mechanisms of neurogenesis recede entering into adulthood. However, with age and insult, these mechanisms boisterously return, resulting in neurodegeneration. This review describes some of the mechanisms involved in synaptogenesis and wiring of the brain from the point of view of the innate immune system and then covers how similar molecular processes return with age and disease, specifically in the context of Alzheimer's disease.