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Retinal Pathology in Alzheimer's Disease (AD)
- Study of pathological changes in the retina of Alzheimer’s disease patients and animal models; investigation of early abnormalities that may appear in the retina prior to the brain and their correlation with brain pathology
The presence of Aβ deposition in postmortem retinas of definitive Alzheimer’s patients and in early-stage cases has been identified for the first time by the Koronyo-Hamaoui Laboratory. In addition, the team developed a noninvasive retinal imaging approach for detection of plaques in live animal models. Administration of curcumin, a natural and safe fluorophore that binds to Aβ, allows detection of retinal plaques in-vivo by very sensitive, noninvasive optical imaging. Results from these studies indicate that the hallmark pathology of AD, Aβ plaque, is not restricted to the brain but also exists in the retina. A correlation was found between the reduction of plaque in the brain and in the retina following immunotherapy in transgenic murine models. Currently, the group is seeking to correlate the accumulation of toxic Aβ to other retinal abnormalities and to visual dysfunctions. Methods such as these may help establish new approaches for early, noninvasive, and definitive diagnosis of AD while enhancing ability to monitor progression and responsiveness to therapeutic interventions.
Figure 1. Identification of Aβ plaques in retinal flatmounts of AD patient and non-AD control. AD retinas show positive labeling of Aβ42-containing plaques. (12F4 mAb; indicated by arrows). The lower right image demonstrates a noninvasive imaging of retinal Aβ plaques (white spots) in live Alzheimer’s transgenic mouse model. (Koronyo-Hamaoui, Koronyo et al., NeuroImage 2011; Koronyo-Hamaoui M, Advances in Neurology and Neurosurgery 2010)
Immunomodulation for AD Therapy
- Study of immunological mechanisms of repair and regeneration in the central nervous system in transgenic rodent models; development of effective immune-modulation therapies to prevent, retard and perhaps cure Alzheimer’s disease
The inflammatory responses that are prominently found in the brains of AD patients and tightly associated with Aβ plaques were perceived as merely detrimental contributors to disease progression. In contrast to this traditional notion, converging evidence, including from the Koronyo-Hamaoui group, has shown that well-controlled adaptive and innate immune responses can limit neurotoxicity, clear cellular debris, enhance neuroprotection, and restore brain homeostasis and cognitive function (Figure 2). Koronyo-Hamaoui’s neuroimmunology laboratory investigates immunological mechanisms of central nervous system (CNS) repair and regeneration in attempt to develop effective and risk-free means of harnessing a protective immune response to treat the pathology associated with neurodegenerative disorders, especially AD.
Figure 2. Neuroinflammation in Alzheimer’s: Detrimental or Beneficial? Alzheimer’s disease brain pathology in a transgenic mouse model; active lesion site typically includes reactive glial cells, such as innate immune (microglia, red) and supportive (astrocytes, cyan) cells surrounding neurotoxic protein aggregates of amyloid plaques (green). Following immunization, a protective phenotype of microglia and macrophages, as well as astrocytes has been observed. In particular, the innate immune cells after immunization are associated with smaller more diffuse Aβ plaques and show an increased capacity to remove Aβ plaques (small images). (Images adopted from Koronyo-Hamaoui et al., J Neurochem 2009)
T Cell-Based Immunization
The Koronyo-Hamaoui Laboratory was able to demonstrate that immunization with glatiramer acetate (GA) or MOG45D loaded on dendritic cells (DC-45D) resulted in significant attenuation of Alzheimer’s-like pathology and improved cognitive performance in murine models. These preclinical studies have shown that immunization evoked a peripheral immune response involving activity of Th2 cells and recruitment of protective monocyte-derived macrophages to regions containing Aβ plaques in the brain. Infiltrating monocyte-derived macrophages are shown to be highly effective in clearing Aβ plaque and in regulating local inflammation. Hence, both GA and DC-MOG45D immunizations were found to target multiple malfunctions occurring in AD; including regulation of detrimental inflammation (i.e., elevated IL-10, TGF-b1, reduced TNF-a), resolution of scar tissue (CSPG, GLT-1 in astrocytes), secretion of Aβ-degrading enzymes (i.e., MMP-9), as well as supporting synaptogenesis and neurogenesis (i.e., Egr-1, IGF-1).
Figure 3. The beneficial effects of GA and DC-45D immunizations in AD transgenic murine models. In addition to retaining cognitive function in immunized ADtg mice, a substantial reduction of brain Aβ plaque burden, astrogliosis and microglial inflammation are observed following immunization. Immunization is also associated with reduced secretion of TNF-α and elevated levels of IL-10 and IGF-1 expressed by microglia and macrophages surrounding Aβ plaque. (Koronyo-Hamaoui et al., J Neurochem 2009; Butovsky, Koronyo-Hamaoui et al., PNAS 2006)
- Transcription factor Egr-1 has been discovered as a mediator of neural survival and neurogenesis in neurodegenerative models
Supplementary search of immune-based mechanisms in the CNS allowed the team to observe restoration and increased formation of newly formed neurons from the brain progenitor pool. In rat models for chronic glaucoma and in mouse models of AD, the lab has unveiled a momentous induction in a newly identified transcription factor (Egr-1) as a result of GA immunization. Egr-1 was correlated with increased neuronal survival in glaucomatous retina, and with reduced brain pathology and increased regeneration and cognitive function in Alzheimer’s models. Nonetheless, the exact mechanism by which GA or MOG45D exhibit neuroprotection is largely unknown. Further research explores other mediators of monocyte recruitment and immune regulation in the transgenic mouse brain.
Figure 4. Enhanced hippocampal EGR-1 immunoreactivity in the dentate gyrus NPCs in ADtg mice following GA immunization. EGR-1 colabels with the newly formed neurons, marked by double cortin (DCX), in the hippocampal dentate gyrus. Coronal brain sections from GA-immunized ADtg mice show overall increased numbers of DCX-positive cells and colocalization of nuclear EGR-1 in these neurons. (Bakalash et al., IOVS 2011)
Therapeutic Role of Monocytes in AD
With the intention of acquiring a more complete understanding of this immune-based approach for AD treatment, the Koronyo-Hamaoui Laboratory experimented with bone marrow-derived monocytes. Upon depletion of bone marrow-derived monocytes in ADtg murine models, an exacerbation of AD-like progression (i.e., more plaques in the brain) was observed. However, following GA or DC-45D immunization, and by enriching the blood with monocyte-derived macrophages or replacing old bone marrow with young wild-type bone marrow-derived monocytes, increased recruitment of blood-borne monocytes was detected in the ADtg mouse brain. Subsequently, there was a reduction in Ab plaques and attenuation of disease progression. Furthermore, the team recognized the subset of bone marrow-derived therapeutic monocytes in AD as inflammatory monocytes. The benefits derived from these inflammatory monocytes are associated with an increased plaque clearance, regulation of inflammation via IL-10, and enhanced catalytic degradation of Ab (i.e., MMP-9). The lab continues to research the activity of these peripheral immune cells in the brain, and their possible impact on mediating tissue-healing processes. (Figure 5. on the left is an image adopted from Koronyo-Hamaoui et al., J Neurochem 2009.)
Targeted Overexpression of Angiotensin Converting Enzyme (ACE) in Macrophages
In addition to the results on the therapeutic role of monocytes, a similar investigation is underway to assess the role of genetically enhanced monocytes in AD. ACE is a peptidase capable of cleaving Aβ1-42 peptide into less toxic peptides. In previous studies, ACE was shown to affect monocytic cell behavior, enhancing these innate immune cells’ ability to combat cancer as well as viral and microbial infections. The Koronyo-Hamaoui Laboratory has found that a genetically modified murine model of AD overexpressing ACE results in a remarkable attenuation of disease progression and cognitive preservation. Degradation of cerebral Ab plaques was associated with their enhanced clearance by monocyte-derived macrophages. Further endeavors will identify and clarify the role of ACE overexpression in the brain regarding the progression of AD along with its applications to immune-based therapy specifically involving monocyte function. Results from these studies may positively impact the availability of effective disease-modifying therapies for AD.
Figure 6. ACE (green) overexpressed by microglia (MG) and CD45high-Mo/MΦ (red) in AD+ACE10/10 mice is associated with smaller and diffused hippocampal Aβ plaques (cyan). In AD+ACE10/10 mice, blood-borne macrophages over express high ACE and are tightly associated with plaque and engulfing Aβ. (Bernstein, Koronyo et al., JCI 2014)
Immune-Based Mechanisms of Repair for Neurodegenerative Disorders
- Pathological aging of peripheral immune system in ALS, Parkinson’s and Alzheimer’s diseases
Key factors involved in a pathological aging of the immune system in the thymus of amyotrophic lateral sclerosis (ALS) mice and human patients have been identified by Maya Koronyo-Hamaoui, PhD, and Michal Schwartz, PhD in collaboration. The results from these studies propose that natural killer T (NKT) cells with decreased hepatic expression of IGF-1 are potential contributors in ALS, and that the liver is a site of a major pathology in this disease. Another study, in collaboration with Dwain Morris-Irvine, PhD, MPH and Christopher Wheeler, PhD, demonstrates that Parkinsonian rodents deficient in T cells perform poorly on behavioral tests and lose selective dopaminergic neurons. These studies may lead to novel immunotherapies and diagnostic biomarkers for Parkinson’s (PD). The combined studies suggest that specific functions of age-related defective T cells can cause AD or PD-like pathology and may contribute to ALS progression, and identifies certain factors as potential targets to counteract neurodegeneration.