Identification of and NLRP3 inflammasome activation in Alzheimer's disease retina.

Emerging evidence implicates bacterial infections, including (Cp), a gram-negative obligate intracellular bacterium responsible for community-acquired pneumonia, in Alzheimer's disease (AD) pathogenesis. However, the involvement of Cp in early and advanced AD in the retina is unknown. Here, we identified the existence and distribution of intracellular Cp inclusions and related NLRP3 inflammasome activation and neurodegeneration in postmortem retinas and brains from 95 human donors.

Identification of and NLRP3 inflammasome activation in Alzheimer's disease retina.

(Cp), an obligate intracellular bacterium, has been implicated in Alzheimer's disease (AD), yet its role in retinal pathology remains unexplored. We analyzed postmortem tissues from 95 human donors and found 2.9-4.

Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer's disease.

Pathological tau isoforms, including hyperphosphorylated tau at serine 396 (pS396-tau) and tau oligomers (Oligo-tau), are elevated in the retinas of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and AD dementia. These patients exhibit significant retinal ganglion cell (RGC) loss, however the presence of tau isoforms in RGCs and their impact on RGC integrity, particularly in early AD, have not been studied. Here, we analyzed retinal superior temporal cross-sections from 25 MCI or AD patients and 16 age- and sex-matched cognitively normal controls.

The effects of enhancing angiotensin converting enzyme in myelomonocytes on ameliorating Alzheimer's-related disease and preserving cognition.

This review examines the role of angiotensin-converting enzyme (ACE) in the context of Alzheimer's disease (AD) and its potential therapeutic value. ACE is known to degrade the neurotoxic 42-residue long alloform of amyloid β-protein (Aβ), a peptide strongly associated with AD. Previous studies in mice, demonstrated that targeted overexpression of ACE in CD115 myelomonocytic cells (ACE10 models) improved their immune responses to effectively reduce viral and bacterial infection, tumor growth, and atherosclerotic plaque.

Retinal pathological features and proteome signatures of Alzheimer's disease.

Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors.

Glatiramer Acetate Immunomodulation: Evidence of Neuroprotection and Cognitive Preservation.

Novel, neuroprotective uses of Copaxone (generic name: glatiramer acetate-GA) are being examined, primarily in neurological conditions involving cognitive decline. GA is a well-studied synthetic copolymer that is FDA-approved for immune-based treatment of relapsing remitting multiple sclerosis (RRMS). Clinical studies have explored the potential mechanism of action (MOA) and outcomes of GA immunization in patients.

Retinal Vasculopathy in Alzheimer's Disease.

The retina has been increasingly investigated as a site of Alzheimer's disease (AD) manifestation for over a decade. Early reports documented degeneration of retinal ganglion cells and their axonal projections. Our group provided the first evidence of the key pathological hallmarks of AD, amyloid β-protein (Aβ) plaques including vascular Aβ deposits, in the retina of AD and mild cognitively impaired (MCI) patients.

Parallels between retinal and brain pathology and response to immunotherapy in old, late-stage Alzheimer's disease mouse models.

Despite growing evidence for the characteristic signs of Alzheimer's disease (AD) in the neurosensory retina, our understanding of retina-brain relationships, especially at advanced disease stages and in response to therapy, is lacking. In transgenic models of AD (APP/PS1; ADtg mice), glatiramer acetate (GA) immunomodulation alleviates disease progression in pre- and early-symptomatic disease stages. Here, we explored the link between retinal and cerebral AD-related biomarkers, including response to GA immunization, in cohorts of old, late-stage ADtg mice.

Alzheimer's Retinopathy: Seeing Disease in the Eyes.

The neurosensory retina emerges as a prominent site of Alzheimer's disease (AD) pathology. As a CNS extension of the brain, the neuro retina is easily accessible for noninvasive, high-resolution imaging. Studies have shown that along with cognitive decline, patients with mild cognitive impairment (MCI) and AD often suffer from visual impairments, abnormal electroretinogram patterns, and circadian rhythm disturbances that can, at least in part, be attributed to retinal damage.

Functional recreation of age-related CD8 T cells in young mice identifies drivers of aging- and human-specific tissue pathology.

Mitigating effects of aging on human health remains elusive because aging impacts multiple systems simultaneously, and because experimental animals exhibit critical aging differences relative to humans. Separation of aging into discrete processes may identify targetable drivers of pathology, particularly when applied to human-specific features. Gradual homeostatic expansion of CD8 T cells dominantly alters their function in aging humans but not in mice.

Effects of IL-34 on Macrophage Immunological Profile in Response to Alzheimer's-Related Aβ Assemblies.

Interleukin-34 (IL-34) is a recently discovered cytokine that acts as a second ligand of the colony stimulating factor 1 receptor (CSF1R) in addition to macrophage colony-stimulating factor (M-CSF). Similar to M-CSF, IL-34 also stimulates bone marrow (BM)-derived monocyte survival and differentiation into macrophages. Growing evidence suggests that peripheral BM-derived monocyte/macrophages (BMMO) play a key role in the physiological clearance of cerebral amyloid β-protein (Aβ).

Activated Bone Marrow-Derived Macrophages Eradicate Alzheimer's-Related Aβ Oligomers and Protect Synapses.

Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to the metastable nature of oligomers. Here, we utilized photo-induced cross-linking to stabilize pure oligomers and study their effects vs.

Identification of early pericyte loss and vascular amyloidosis in Alzheimer's disease retina.

Pericyte loss and deficient vascular platelet-derived growth factor receptor-β (PDGFRβ) signaling are prominent features of the blood-brain barrier breakdown described in Alzheimer's disease (AD) that can predict cognitive decline yet have never been studied in the retina. Recent reports using noninvasive retinal amyloid imaging, optical coherence tomography angiography, and histological examinations support the existence of vascular-structural abnormalities and vascular amyloid β-protein (Aβ) deposits in retinas of AD patients. However, the cellular and molecular mechanisms of such retinal vascular pathology were not previously explored.

Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease.

Targeted overexpression of angiotensin-converting enzyme (ACE), an amyloid-β protein degrading enzyme, to brain resident microglia and peripheral myelomonocytes (ACE10 model) substantially diminished Alzheimer's-like disease in double-transgenic APPSWE/PS1ΔE9 (AD+) mice. In this study, we explored the impact of selective and transient angiotensin-converting enzyme overexpression on macrophage behaviour and the relative contribution of bone marrow-derived ACE10 macrophages, but not microglia, in attenuating disease progression. To this end, two in vivo approaches were applied in AD+ mice: (i) ACE10/GFP+ bone marrow transplantation with head shielding; and (ii) adoptive transfer of CD115+-ACE10/GFP+ monocytes to the peripheral blood.

HER3-targeted protein chimera forms endosomolytic capsomeres and self-assembles into stealth nucleocapsids for systemic tumor homing of RNA interference in vivo.

RNA interference represents a potent intervention for cancer treatment but requires a robust delivery agent for transporting gene-modulating molecules, such as small interfering RNAs (siRNAs). Although numerous molecular approaches for siRNA delivery are adequate in vitro, delivery to therapeutic targets in vivo is limited by payload integrity, cell targeting, efficient cell uptake, and membrane penetration. We constructed nonviral biomaterials to transport small nucleic acids to cell targets, including tumor cells, on the basis of the self-assembling and cell-penetrating activities of the adenovirus capsid penton base.

Resistance to receptor-blocking therapies primes tumors as targets for HER3-homing nanobiologics.

Resistance to anti-tumor therapeutics is an important clinical problem. Tumor-targeted therapies currently used in the clinic are derived from antibodies or small molecules that mitigate growth factor activity. These have improved therapeutic efficacy and safety compared to traditional treatment modalities but resistance arises in the majority of clinical cases.

A novel role for osteopontin in macrophage-mediated amyloid-β clearance in Alzheimer's models.

Osteopontin (OPN), a matricellular immunomodulatory cytokine highly expressed by myelomonocytic cells, is known to regulate immune cell migration, communication, and response to brain injury. Enhanced cerebral recruitment of monocytes achieved through glatiramer acetate (GA) immunization or peripheral blood enrichment with bone marrow (BM)-derived CD115 monocytes (Mo) curbs amyloid β-protein (Aβ) neuropathology and preserves cognitive function in murine models of Alzheimer's disease (ADtg mice). To elucidate the beneficial mechanisms of these immunomodulatory approaches in AD, we focused on the potential role of OPN in macrophage-mediated Aβ clearance.

ZEB1 regulates glioma stemness through LIF repression.

The identification of a stem cell regulatory gene which is aberrantly expressed in glioma and associated with patient survival would increase the understanding of the role of glioma cancer stem cells (GCSCs) in the virulence of gliomas. Interrogating the genomes of over 4000 brain cancers we identified ZEB1 deletion in ~15% (grade II and III) and 50% of glioblastomas. Meta-analysis of ZEB1 copy number status in 2,988 cases of glioma revealed disruptive ZEB1 deletions associated with decreased survival.