Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer's disease.

Preclinical and clinical data support the use of focused ultrasound (FUS), in the presence of intravenously injected microbubbles, to safely and transiently increase the permeability of the blood-brain barrier (BBB). FUS-induced BBB permeability has been shown to enhance the bioavailability of administered intravenous therapeutics to the brain. Ideal therapeutics candidates for this mode of delivery are those capable of inducing benefits peripherally following intravenous injection and in the brain at FUS-targeted areas. In Alzheimer's disease, intravenous immunoglobulin (IVIg), a fractionated human blood product containing polyclonal antibodies, act as immunomodulator peripherally and centrally, and it can reduce amyloid pathology in the brain. Using the TgCRND8 mouse model of amyloidosis, we tested whether FUS can improve the delivery of IVIg, administered intravenously (0.4 g/kg), to the hippocampus and reach an effective dose to reduce amyloid plaque pathology and promote neurogenesis. Our results show that FUS-induced BBB permeability is required to deliver a significant amount of IVIg (489 ng/mg) to the targeted hippocampus of TgCRN8 mice. Two IVIg-FUS treatments, administered at days 1 and 8, significantly increased hippocampal neurogenesis by 4-, 3-, and 1.5-fold in comparison to saline, IVIg alone, and FUS alone, respectively. Amyloid plaque pathology was significantly reduced in all treatment groups: IVIg alone, FUS alone, and IVIg-FUS. Putative factors promoting neurogenesis in response to IVIg-FUS include the down-regulation of the proinflammatory cytokine TNF-α in the hippocampus. In summary, FUS was required to deliver an effective dose of IVIg to promote hippocampal neurogenesis and modulate the inflammatory milieu.

The expression of apoptosis inducing factor (AIF) is associated with aging-related cell death in the cortex but not in the hippocampus in the TgCRND8 mouse model of Alzheimer's disease.

BACKGROUND: Recent evidence has suggested that Alzheimer's disease (AD)-associated neuronal loss may occur via the caspase-independent route of programmed cell death (PCD) in addition to caspase-dependent mechanisms. However, the brain region specificity of caspase-independent PCD in AD-associated neurodegeneration is unknown. We therefore used the transgenic CRND8 (TgCRND8) AD mouse model to explore whether the apoptosis inducing factor (AIF), a key mediator of caspase-independent PCD, contributes to cell loss in selected brain regions in the course of aging. RESULTS: Increased expression of truncated AIF (tAIF), which is directly responsible for cell death induction, was observed at both 4- and 6-months of age in the cortex. Concomitant with the up-regulation of tAIF was an increase in the nuclear translocation of this protein. Heightened tAIF expression or translocation was not observed in the hippocampus or cerebellum, which were used as AD-vulnerable and relatively AD-spared regions, respectively. The cortical alterations in tAIF levels were accompanied by increased Bax expression and mitochondrial translocation. This effect was preceded by a significant reduction in ATP content and an increase in reactive oxygen species (ROS) production, detectable at 2 months of age despite negligible amounts of amyloid-beta peptides (Aß). CONCLUSIONS: Taken together, these data suggest that AIF is likely to play a region-specific role in AD-related caspase-independent PCD, which is consistent with aging-associated mitochondrial impairment and oxidative stress.

Alterations in hippocampal network oscillations and theta-gamma coupling arise before Aß overproduction in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by memory impairments. Brain oscillatory activity is critical for cognitive function and is altered in AD patients. Recent evidence suggests that accumulation of soluble amyloid-beta (Aß) induces reorganization of hippocampal networks. However, whether fine changes in network activity might be present at very early stages, before Aß overproduction, remains to be determined. We therefore assessed whether theta and gamma oscillations and their cross-frequency coupling, which are known to be essential for normal memory function, were precociously altered in the hippocampus. Electrophysiological field potential recordings were performed using complete hippocampal preparations in vitro from young transgenic CRND8 mice, a transgenic mouse model of AD. Our results indicate that a significant proportion of 1-month-old TgCRND8 mice showed robust alterations of theta-gamma cross-frequency coupling in the principal output region of the hippocampus, the subiculum. In addition we showed that, compared to controls, these mice expressed negligible levels of Aß. Finally, these network alterations were not due to genetic factors as 15-day-old animals did not exhibit theta-gamma coupling alterations. Thus, initial alterations in hippocampal network activity arise before Aß accumulation and may represent an early biomarker for AD.

Pre-symptomatic synaptic dysfunction and longitudinal decay of hippocampal synaptic function in APPPS1 mouse model of Alzheimer's disease is sex-independent.

Alzheimer's disease (AD) is an incurable, age-related and progressive neurodegenerative disease characterized by cognitive impairments. Deficits in synaptic plasticity were reported in various models of AD-like pathology and are considered as an early contributing factor of cognitive impairment. However, the majority of previous studies were focused on overt, symptomatic stages of pathology and assessed long-term potentiation (LTP), whereas long-term depression (LTD) was much less investigated and the precise nature of its involvement remains poorly defined. To better understand the earliest synaptic dysfunctions along the pre-symptomatic stage of AD-like pathology, we performed a detailed analysis of underlying mechanisms and quantified basal synaptic activity, presynaptic release probability, and synaptic plasticity such as post-tetanic potentiation (PTP), as well as LTP and LTD. These parameters were studied in APPPS1 mouse model at two time points (early- and mid-) along the pre-symptomatic stage, which were compared with alterations monitored at two later time-points, i.e. the onset of cognitive deficits and the overt stage of full-blown pathology. Because sex is known to be an instrumental biological parameter in AD pathophysiology, all alterations were assessed in both males and females. Our data show that, as compared to wild-type (WT) littermates, initial neuronal hyperexcitability, seen at early pre-symptomatic stage shifts subsequently towards hypoexcitability at mid-pre-symptomatic stage and remains impaired at advanced stages. The pre-symptomatic changes also involve increased synaptic plasticity as assessed by paired-pulse facilitation (PPF), which returns to basal level at the onset of pathology and remains stable afterwards. Synaptic plasticity is impaired by mid-pre-symptomatic stage and manifests as lowered LTP and absence of LTD induction, the latter being reported here for the first time. Observed LTP and LTD impairments both persist in older APPPS1 mice. Remarkably, none of the observed differences was gender-dependent. Altogether, our data evidence that major impairments in basal synaptic efficacy and plasticity are detectable already during mid-pre-symptomatic stage of AD-like pathogenesis and likely involve hyperexcitability as the underlying mechanism. Our study also uncovers synaptic alterations that may become critical read-outs for testing the efficiency of novel, pre-symptomatic stage-targeted therapies for AD.

Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer's disease.

BACKGROUND: The implication of gut microbiota in the control of brain functions in health and disease is a novel, currently emerging concept. Accumulating data suggest that the gut microbiota exert its action at least in part by modulating neuroinflammation. Given the link between neuroinflammatory changes and neuronal activity, it is plausible that gut microbiota may affect neuronal functions indirectly by impacting microglia, a key player in neuroinflammation. Indeed, increasing evidence suggests that interplay between microglia and synaptic dysfunction may involve microbiota, among other factors. In addition to these indirect microglia-dependent actions of microbiota on neuronal activity, it has been recently recognized that microbiota could also affect neuronal activity directly by stimulation of the vagus nerve. MAIN MESSAGES: The putative mechanisms of the indirect and direct impact of microbiota on neuronal activity are discussed by focusing on Alzheimer's disease, one of the most studied neurodegenerative disorders and the prime cause of dementia worldwide. More specifically, the mechanisms of microbiota-mediated microglial alterations are discussed in the context of the peripheral and central inflammation cross-talk. Next, we highlight the role of microbiota in the regulation of humoral mediators of peripheral immunity and their impact on vagus nerve stimulation. Finally, we address whether and how microbiota perturbations could affect synaptic neurotransmission and downstream cognitive dysfunction. CONCLUSIONS: There is strong increasing evidence supporting a role for the gut microbiome in the pathogenesis of Alzheimer's disease, including effects on synaptic dysfunction and neuroinflammation, which contribute to cognitive decline. Putative early intervention strategies based on microbiota modulation appear therapeutically promising for Alzheimer's disease but still require further investigation.

Concomitant Retinal Alterations in Neuronal Activity and TNFα Pathway Are Detectable during the Pre-Symptomatic Stage in a Mouse Model of Alzheimer's Disease.

The pre-symptomatic stage of Alzheimer's disease (AD) is associated with increased amyloid-ß (Aß) precursor protein (APP) processing and Aß accumulation in the retina and hippocampus. Because neuronal dysfunctions are among the earliest AD-related alterations, we asked whether they are already detectable in the retina during the pre-symptomatic stage in a APPswePS1dE9 (APP/PS1) mouse model. The age chosen for the study (3-4 months) corresponds to the pre-symptomatic stage because no retinal Aß was detected, in spite of the presence of ßCTF (the first cleavage product of APP). We observed an increase in ERG amplitudes in APP/PS1 mice in comparison to the controls, which indicated an increased retinal neuron activity. These functional changes coincided with an increased expression of retinal TNFα and its receptors type-1 (TNFR1). Consistently, the IkB expression increased in APP/PS1 mice with a greater proportion of the phosphorylated protein (P-IkB) over total IkB, pointing to the putative involvement of the NFkB pathway. Because TNFα plays a crucial role in the control of neuronal excitability, it is likely that, as in the hippocampus, TNFα signaling via the TNFR1/NFkB pathway may be also involved in early, AD-associated, retinal neuron hyperexcitability. These results further demonstrate the interest of the retina for early disease detection with a potential to assess future therapeutic strategies.

Neuroinflammation: A Possible Link Between Chronic Vascular Disorders and Neurodegenerative Diseases.

Various age-related diseases involve systemic inflammation, i.e. a stereotyped series of acute immune system responses, and aging itself is commonly associated with low-grade inflammation or inflamm'aging. Neuroinflammation is defined as inflammation-like processes inside the central nervous system, which this review discusses as a possible link between cardiovascular disease-related chronic inflammation and neurodegenerative diseases. To this aim, neuroinflammation mechanisms are first summarized, encompassing the cellular effectors and the molecular mediators. A comparative survey of the best-known physiological contexts of neuroinflammation (neurodegenerative diseases and transient ischemia) reveals some common features such as microglia activation. The recently published transcriptomic characterizations of microglia have pointed a marker core signature among neurodegenerative diseases, but also unraveled the discrepancies with neuroinflammations related with acute diseases of vascular origin. We next review the links between systemic inflammation and neuroinflammation, beginning with molecular features of respective pro-inflammatory cells, i.e. macrophages and microglia. Finally, we point out a gap of knowledge concerning the atherosclerosis-related neuroinflammation, which is for the most surprising given that atherosclerosis is established as a major risk factor for neurodegenerative diseases.

α7 Nicotinic receptor activation reduces ß-amyloid-induced apoptosis by inhibiting caspase-independent death through phosphatidylinositol 3-kinase signaling.

The neurotoxicity of amyloid-ß (Aß) involves caspase-dependent and -independent programmed cell death. The latter is mediated by the nuclear translocation of the mitochondrial flavoprotein apoptosis inducing factor (AIF). Nicotine has been shown to decrease Aß neurotoxicity via inhibition of caspase-dependent apoptosis, but it is unknown if its neuroprotection is mediated through caspase-independent pathways. In the present study, pre-treatment with nicotine in rat cortical neuronal culture markedly reduced Aß(1-42) induced neuronal death. This effect was accompanied by a significant reduction of mitochondrial AIF release and its subsequent nuclear translocation as well as significant inhibition of cytochrome c release and caspase 3 activation. Pre-treatment with selective α7nicotinic acetylcholine receptor(nAChR) antagonist (methyllycaconitine), but not the α4 nAChR antagonist (dihydro-ß-erythroidine), could prevent the neuroprotective effect of nicotine on AIF release/translocation, suggesting that nicotine inhibits the caspase-independent death pathway in a α7 nAChR-dependent fashion. Furthermore, the neuroprotective action of nicotine on AIF release/translocation was suppressed by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor. Pre-treatment with nicotine significantly restored Akt phosphorylation, an effector of PI3K, in Aß(1-42) -treated neurons. These findings indicate that the α7 nAChR activation and PI3K/Akt transduction signaling contribute to the neuroprotective effects of nicotine against Aß-induced cell death by modulating caspase-independent death pathways.

Evidence for the involvement of apoptosis-inducing factor-mediated caspase-independent neuronal death in Alzheimer disease.

Accumulating evidence suggests the involvement of caspase-dependent and -independent mechanisms in neuronal cell death in Alzheimer disease (AD). The apoptosis-inducing factor (AIF) is a mitochondrial oxido-reductase originally characterized as a mediator of caspase-independent programmed cell death (PCD). In this postmortem study, we investigated the distribution of AIF and its possible morphological association with pathological features in the hippocampus, as well as entorhinal and medial gyrus of temporal cortices of late stage AD, dementia with Lewy bodies (DLB), and control subjects. In comparison with controls, a significant increase in neuronal AIF immunoreactivity (AIF-ir) was observed in the hippocampus and the superficial layers of entorhinal and medial gyrus of temporal cortices in AD--but not DLB--samples. AIF-ir in neuronal nuclei was also significantly more widespread in AD compared with control and DLB samples. Furthermore, AIF-ir was found to be colocalized with neurofibrillary tangles (NFTs) in AD brains. Interestingly, a significant positive correlation was seen between nuclear AIF-ir and Braak stage in CA1 of the hippocampus as well as in entorhinal and temporal cortices in AD samples. These data show for the first time: (1) the nuclear localization of AIF in the AD brain and (2) its colocalization with NFTs, suggesting a possible involvement of AIF-mediated caspase-independent PCD, at least in the late stage of this neuropathology.

Synaptic Activity and (Neuro)Inflammation in Alzheimer's Disease: Could Exosomes be an Additional Link?

Nanosized extracellular vesicles, known as exosomes, are produced by all cell types in mammalian organisms and have been recently involved in neurodegeneration. In the brain, both glia and neurons give rise to exosomes, which contribute to their intercellular communication. In addition, brain-derived exosomes have a remarkable property to cross the blood-brain-barrier bi-directionally. In this line, exosomes of central origin have been identified in peripheral circulation and already considered as putative blood biomarkers of neurodegenerative diseases, including Alzheimer's disease (AD). Moreover, tentative use of exosomes as vehicle for the clearance of brain-born toxic proteins or, conversely, neuroprotective drug delivery, was also envisaged. However, little is known about the precise role of exosomes in the control and regulation of neuronal functions. Based on the presence of subunits of glutamate receptors in neuron-derived exosomes on one hand, and complement proteins in astrocyte-derived exosomes on the other hand, we hypothesize that exosomes may participate in the control of neuronal excitability via inflammatory-like mechanisms both at the central level and from the periphery. In this review, we will focus on AD and discuss the mechanisms by which exosomes of neuronal, glial, and/or peripheral origin could impact on neuronal excitability either directly or indirectly.

The Vagal Autonomic Pathway of COVID-19 at the Crossroad of Alzheimer's Disease and Aging: A Review of Knowledge.

Coronavirus Disease 2019 (COVID-19) pandemic-triggered mortality is significantly higher in older than in younger populations worldwide. Alzheimer's disease (AD) is related to aging and was recently reported to be among the major risk factors for COVID-19 mortality in older people. The symptomatology of COVID-19 indicates that lethal outcomes of infection rely on neurogenic mechanisms. The present review compiles the available knowledge pointing to the convergence of COVID-19 complications with the mechanisms of autonomic dysfunctions in AD and aging. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is prone to neuroinvasion from the lung along the vagus nerve up to the brainstem autonomic nervous centers involved in the coupling of cardiovascular and respiratory rhythms. The brainstem autonomic network allows SARS-CoV-2 to trigger a neurogenic switch to hypertension and hypoventilation, which may act in synergy with aging- and AD-induced dysautonomias, along with an inflammatory "storm". The lethal outcomes of COVID-19, like in AD and unhealthy aging, likely rely on a critical hypoactivity of the efferent vagus nerve cholinergic pathway, which is involved in lowering cardiovascular pressure and systemic inflammation tone. We further discuss the emerging evidence supporting the use of 1) the non-invasive stimulation of vagus nerve as an additional therapeutic approach for severe COVID-19, and 2) the demonstrated vagal tone index, i.e., heart rate variability, via smartphone-based applications as a non-serological low-cost diagnostic of COVID-19. These two well-known medical approaches are already available and now deserve large-scale testing on human cohorts in the context of both AD and COVID-19.

Apoptosis-inducing factor: a matter of neuron life and death.

The mitochondrial flavoprotein apoptosis-inducing factor (AIF) is the main mediator of caspase-independent apoptosis-like programmed cell death. Upon pathological permeabilization of the outer mitochondrial membrane, AIF is translocated to the nucleus, where it participates in chromatin condensation and is associated to large-scale DNA fragmentation. Heavy down-regulation of AIF expression in mutant mice or reduced AIF expression achieved with small interfering RNA (siRNA) provides neuroprotection against acute neurodegenerative insults. Paradoxically, in addition to its pro-apoptotic function, AIF likely plays an anti-apoptotic role by regulating the production of reactive oxygen species (ROS) via its putative oxidoreductase and peroxide scavenging activities. In this review, we discuss accumulating evidence linking AIF to both acute and chronic neurodegenerative processes by emphasising mechanisms underlying the dual roles apparently played by AIF in these processes.

Common Pathological Mechanisms and Risk Factors for Alzheimer's Disease and Type-2 Diabetes: Focus on Inflammation.

BACKGROUND: Diabetes is considered as a risk factor for Alzheimer's Disease, but it is yet unclear whether this pathological link is reciprocal. Although Alzheimer's disease and diabetes appear as entirely different pathological entities affecting the Central Nervous System and a peripheral organ (pancreas), respectively, they share a common pathological core. Recent evidence suggests that in the pancreas in the case of diabetes, as in the brain for Alzheimer's Disease, the initial pathological event may be the accumulation of toxic proteins yielding amyloidosis. Moreover, in both pathologies, amyloidosis is likely responsible for local inflammation, which acts as a driving force for cell death and tissue degeneration. These pathological events are all inter-connected and establish a vicious cycle resulting in the progressive character of both pathologies. OBJECTIVE: To address the literature supporting the hypothesis of a common pathological core for both diseases. DISCUSSION: We will focus on the analogies and differences between the disease-related inflammatory changes in a peripheral organ, such as the pancreas, versus those observed in the brain. Recent evidence suggesting an impact of peripheral inflammation on neuroinflammation in Alzheimer's disease will be presented. CONCLUSION: We propose that it is now necessary to consider whether neuroinflammation in Alzheimer's disease affects inflammation in the pancreas related to diabetes.

Leptin-mediated decrease of cyclin A2 and increase of cyclin D1 expression: relevance for the control of prepubertal rat Leydig cell division and differentiation.

The number of adult Leydig cells is one of the factors controlling testosterone secretion by sexually mature testis, and it depends on the proliferative capacity of prepubertal Leydig cells. We investigated here whether this capacity is controlled by leptin because this hormone regulates proliferation in other cell types and has a crucial role in male fertility. Our data show that prebupertal Leydig cells express the Ob/Rb form of leptin receptor and are thus direct targets of this hormone. The analysis of G1/S-phase cyclins by quantitative (real-time) RT-PCR and Western blot points to the leptin-induced decrease in cyclin A2 and subsequent increase in cyclin D1 expression that precedes a leptin-triggered decrease in the number of prepubertal Leydig cells. Quantitative assessments of DNA synthesis by bromodeoxyuridine incorporation and of cycling cell population by Ki67 immunocytochemistry indicate that leptin decreases the cell number by inhibiting cell division and increases mRNA levels of Leydig cell differentiation markers such as relaxin-like factor. Immunohistochemistry of cyclin D1 and relaxin-like factor pointed to the parallel increase of their expression coinciding with the onset of Leydig cell differentiation. Moreover, leptin-treated Leydig cells display increased expression of another differentiation marker (3beta-hydroxysteroid dehydrogenase) that is abolished by knocking down cyclin D1 with small interference RNA. Altogether, our data show that leptin inhibits division of prepubertal Leydig cells via a cyclin D-independent mechanism and suggest that cyclin D1 might be involved in leptin-induced differentiation of Leydig cells.

Molecular basis of programmed cell death involved in neurodegeneration.

Rapid progress in understanding the molecular basis of neurodegeneration has been tightly linked with recent discoveries in the field of programmed cell death (PCD). Analysis of PCD in neuronal demise has led to identification of several associated phenomena, such as re-initiation of the cell cycle and the key role of oxidative stress, although putative causal relationships between these events are still debatable. These issues are reviewed here in the context of acute and chronic neurodegenerative processes. In addition, newly emerging concepts concerning cell-cycle re-initiation are discussed in terms of their potential impact on the development of more effective therapeutic strategies.

Epidermal growth factor triggers an original, caspase-independent pituitary cell death with heterogeneous phenotype.

Programmed cell death (PCD) is physiologically involved in the regulation of cell division and differentiation. It encompasses caspase-dependent mitochondrial and nonmitochondrial pathways. Additional caspase-independent pathways have been characterized in mitochondrial PCDs but remain hypothetical in nonmitochondrial PCDs. Epidermal growth factor (EGF) has been shown to inhibit division of pituitary somato-lactotrope cells occurring in parallel with EGF-mediated differentiation of these precursors into lactotrope cells. We show here that in somato-lactotrope pituitary cell line GH4C1, EGF triggers a PCD characterized by an apoptosis-like DNA fragmentation, insensitivity to broad-range caspase inhibitors, and absence of either cytochrome c or apoptosis-inducing factor release from mitochondria. Dying cells display loose chromatin clustering and numerous cytoplasmic vacuoles, a fraction of which are autophagic, thus conferring a heterogeneous phenotype to this PCD. Moreover, overexpression of cell death inhibitor Bcl-2 prevented not only the EGF-induced PCD but also its prodifferentiation effects, thus pointing to a mechanistic relationship existing between these two phenomena. Overall, the characterized differentiation-linked cell death represents an original form of caspase-independent PCD. The mechanisms underlying this PCD involve combinatorial engagement of discrete death effectors leading to a heterogeneous death phenotype that might be evolutionary related to PCD seen during the differentiation of some unicellular organisms.

Seeing Early Signs of Alzheimer's Disease Through the Lens of the Eye.

BACKGROUND: Alzheimer's disease (AD) develops undetected for years due to the lack of early diagnostic biomarkers. In advanced AD, visual deficits related to cortical neurodegeneration are well recognized, but recent studies have identified that the retina could be affected prior to vulnerable brain areas such as cortex and hippocampus. In this review, we discuss a new evidence suggesting that functional alterations in the retina may become the earliest diagnostic biomarkers for AD. METHODS: Analytical analysis of bibliographic databases for peer-reviewed research literature was performed by focusing on the review topic and using standard inclusion/exclusion criteria in the context of the given conceptual framework i.e., that synaptic dysfunction within the retina may be reminiscent of changes within the brain. RESULTS: A total of 134 papers were included in the review, the majority (52) dealing with the earliest dysfunction of synaptic and neuronal networks in vulnerable brain areas to point out how they may inspire the analogous research in the retina. The general aspects of retina organization and the retinal alterations in the late stages of AD are then discussed based on the analysis of the next 40 and 31 papers, respectively. We finally present evidence (11 papers) indicating why putative retinal synaptic dysfunction holds the potential to become the earliest sign of AD, allowing for a non-invasive and easy detection using modern imaging and functional techniques. CONCLUSION: Translation of these findings to clinical diagnosis could lead to earlier therapeutic interventions and, consequently, better chances to delay or halt AD progression.

Amyloidosis in Retinal Neurodegenerative Diseases.

As a part of the central nervous system, the retina may reflect both physiological processes and abnormalities related to pathologies that affect the brain. Amyloidosis due to the accumulation of amyloid-beta (Aß) was initially regarded as a specific and exclusive characteristic of neurodegenerative alterations seen in the brain of Alzheimer's disease (AD) patients. More recently, it was discovered that amyloidosis-related alterations, similar to those seen in the brain of Alzheimer's patients, also occur in the retina. Remarkably, these alterations were identified not only in primary retinal pathologies, such as age-related macular degeneration (AMD) and glaucoma, but also in the retinas of Alzheimer's patients. In this review, we first briefly discuss the biogenesis of Aß, a peptide involved in amyloidosis. We then discuss some pathological aspects (synaptic dysfunction, mitochondrial failure, glial activation, and vascular abnormalities) related to the neurotoxic effects of Aß. We finally highlight common features shared by AD, AMD, and glaucoma in the context of Aß amyloidosis and further discuss why the retina, due to the transparency of the eye, can be considered as a "window" to the brain.

Expression of Phenotypic Astrocyte Marker Is Increased in a Transgenic Mouse Model of Alzheimer's Disease versus Age-Matched Controls: A Presymptomatic Stage Study.

Recent mouse studies of the presymptomatic stage of Alzheimer's disease (AD) have suggested that proinflammatory changes, such as glial activation and cytokine induction, may occur already at this early stage through unknown mechanisms. Because TNFα contributes to increased Aß production from the Aß precursor protein (APP), we assessed a putative correlation between APP/Aß and TNFα during the presymptomatic stage as well as early astrocyte activation in the hippocampus of 3-month-old APPswe/PS1dE9 mice. While Western blots revealed significant APP expression, Aß was not detectable by Western blot or ELISA attesting that 3-month-old, APPswe/PS1dE9 mice are at a presymptomatic stage of AD-like pathology. Western blots were also used to show increased GFAP expression in transgenic mice that positively correlated with both TNFα and APP, which were also mutually correlated. Subregional immunohistochemical quantification of phenotypic (GFAP) and functional (TSPO) markers of astrocyte activation indicated a selective and significant increase in GFAP-immunoreactive (IR) cells in the dentate gyrus of APPswe/PS1dE9 mice. Our data suggest that subtle morphological and phenotypic alterations, compatible with the engagement of astrocyte along the activation pathway, occur in the hippocampus already at the presymptomatic stage of AD.