Drosophila Eye Model to Study Neuroprotective Role of CREB Binding Protein (CBP) in Alzheimer’s Disease

Cutler, T S; Sarkar, Ankita; Moran, Michael T; Steffensmeier, Andrew M.; Puli, Oorvashi Roy; Mancini, Greg; Tare, Meghana; Gogia, Neha; Singh, Amit

doi:10.1371/journal.pone.0137691

Cited by 52 publications

(41 citation statements)

References 85 publications

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“…Many of these findings mirror those recorded in AD patients (Table 3) [5, 6, 30, 39, 48, 52, 56, 72, 117, 123, 139, 148, 152, 154, 178, 184]. …”

Section: Non-specific Ocular Abnormalities In Animal Models Of Adsupporting

confidence: 72%

“…Thickness reduction and vascular changes[178]DrosophilahAβ 42 tgLens. Fission resulting in glazed-eye phenotype and reduced compound eye; swelling, organelle disorganization, opacity[39, 56]MouseTg2576, hAβPPtg/tgOtherMouseTg2576, APP/PS1, ApoE4Retina. Double nuclei and hypertrophy in RPE; increased ATP q release; Mitochondrial swelling, crista fragmentation and reduced complexity[75, 151, 152, 178, 184]RatTgF344-ADMouseApoE4Choroid.…”

Section: Non-specific Ocular Abnormalities In Animal Models Of Admentioning

confidence: 99%

“…Amacrine cell apoptosis has also been noted in the retina of the APP SWE /PS1 ΔE9 mouse [61]. Evidence from drosophila studies supportive of ocular degeneration in AD models has indicated severe photoreceptor abnormality, lens fission, and axonal degeneration in the optic nerve [30, 39, 52, 72]. …”

Section: Non-specific Ocular Abnormalities In Animal Models Of Admentioning

confidence: 99%

“…While synaptic density in the Tg2576 mouse has shown no change in either pre- or post-synaptic markers [184], synaptic loss and impairment, typically related to cognitive deficits when observed in the brain, have been reported in the ApoE4 mouse retina [5, 6]. Changes observed outside of ocular CNS tissues in rodent and fly eyes have included thinning of the choroid [178], as well as cellular swelling, organelle disorganization, and opacity in the lens [39, 56]. Furthermore, altered expression levels of various proteins and mRNA transcripts essential to normal cell function have been detected, including a report of increased ATP release in the retina of an APP/PS1 mouse model [151].…”

Section: Non-specific Ocular Abnormalities In Animal Models Of Admentioning

confidence: 99%

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Ocular indicators of Alzheimer’s: exploring disease in the retina

et al. 2016

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Although historically perceived as a disorder confined to the brain, our understanding of Alzheimer’s disease (AD) has expanded to include extra-cerebral manifestation, with mounting evidence of abnormalities in the eye. Among ocular tissues, the retina, a developmental outgrowth of the brain, is marked by an array of pathologies in patients suffering from AD, including nerve fiber layer thinning, degeneration of retinal ganglion cells, and changes to vascular parameters. While the hallmark pathological signs of AD, amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFT) comprising hyperphosphorylated tau (pTau) protein, have long been described in the brain, identification of these characteristic biomarkers in the retina has only recently been reported. In particular, Aβ deposits were discovered in post-mortem retinas of advanced and early stage cases of AD, in stark contrast to non-AD controls. Subsequent studies have reported elevated Aβ42/40 peptides, morphologically diverse Aβ plaques, and pTau in the retina. In line with the above findings, animal model studies have reported retinal Aβ deposits and tauopathy, often correlated with local inflammation, retinal ganglion cell degeneration, and functional deficits. This review highlights the converging evidence that AD manifests in the eye, especially in the retina, which can be imaged directly and non-invasively. Visual dysfunction in AD patients, traditionally attributed to well-documented cerebral pathology, can now be reexamined as a direct outcome of retinal abnormalities. As we continue to study the disease in the brain, the emerging field of ocular AD warrants further investigation of how the retina may faithfully reflect the neurological disease. Indeed, detection of retinal AD pathology, particularly the early presenting amyloid biomarkers, using advanced high-resolution imaging techniques may allow large-scale screening and monitoring of at-risk populations.

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“…Many of these findings mirror those recorded in AD patients (Table 3) [5, 6, 30, 39, 48, 52, 56, 72, 117, 123, 139, 148, 152, 154, 178, 184]. …”

Section: Non-specific Ocular Abnormalities In Animal Models Of Adsupporting

confidence: 72%

Section: Non-specific Ocular Abnormalities In Animal Models Of Admentioning

confidence: 99%

Section: Non-specific Ocular Abnormalities In Animal Models Of Admentioning

confidence: 99%

Section: Non-specific Ocular Abnormalities In Animal Models Of Admentioning

confidence: 99%

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Ocular indicators of Alzheimer’s: exploring disease in the retina

et al. 2016

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“…As per the amyloid hypothesis, the accumulation of the Aβ42 peptides into plaques initiates a pathological cascade eventually leading to neurodegeneration (Tare et al, 2011;Selkoe and Hardy, 2016;Yeates et al, 2019). Since this hypothesis was postulated, several signaling pathways and genetic modifiers have been implicated in Aβ42-mediated neurodegeneration (Moran et al, 2013;Steffensmeier et al, 2013;Cutler et al, 2015;Yeates et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

A Positive Feedback Loop of Hippo- and c-Jun-Amino-Terminal Kinase Signaling Pathways Regulates Amyloid-Beta-Mediated Neurodegeneration

Irwin

Tare

Singh

et al. 2020

Front. Cell Dev. Biol.

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Alzheimer's disease (AD, OMIM: 104300) is an age-related disorder that affects millions of people. One of the underlying causes of AD is generation of hydrophobic amyloid-beta 42 (Aβ42) peptides that accumulate to form amyloid plaques. These plaques induce oxidative stress and aberrant signaling, which result in the death of neurons and other pathologies linked to neurodegeneration. We have developed a Drosophila eye model of AD by targeted misexpression of human Aβ42 in the differentiating retinal neurons, where an accumulation of Aβ42 triggers a characteristic neurodegenerative phenotype. In a forward deficiency screen to look for genetic modifiers, we identified a molecularly defined deficiency, which suppresses Aβ42-mediated neurodegeneration. This deficiency uncovers hippo (hpo) gene, a member of evolutionarily conserved Hippo signaling pathway that regulates growth. Activation of Hippo signaling causes cell death, whereas downregulation of Hippo signaling triggers cell proliferation. We found that Hippo signaling is activated in Aβ42-mediated neurodegeneration. Downregulation of Hippo signaling rescues the Aβ42-mediated neurodegeneration, whereas upregulation of Hippo signaling enhances the Aβ42-mediated neurodegeneration phenotypes. It is known that c-Jun-amino-terminal kinase (JNK) signaling pathway is upregulated in AD. We found that activation of JNK signaling enhances the Aβ42-mediated neurodegeneration, whereas downregulation of JNK signaling rescues the Aβ42-mediated neurodegeneration. We tested the nature of interactions between Hippo signaling and JNK signaling in Aβ42-mediated neurodegeneration using genetic epistasis approach. Our data suggest that Hippo signaling and JNK signaling, two independent signaling pathways, act synergistically upon accumulation of Aβ42 plaques to trigger cell death. Our studies demonstrate a novel role of Hippo signaling pathway in Aβ42-mediated neurodegeneration.

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Proximal fate marker homothorax marks the lateral extension of stalk‐eyed fly Cyrtodopsis whitei

Singh

Gogia

Chang

et al. 2019

Genesis

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The placement of eyes on insect head is an important evolutionary trait. The stalk-eyed fly, Cyrtodopsis whitei, exhibits a hypercephaly phenotype where compound eyes are located on lateral extension from the head while the antennal segments are placed inwardly on this stalk. This stalk-eyed phenotype is characteristic of the family Diopsidae in the Diptera order and dramatically deviates from other dipterans, such as Drosophila.Like other insects, the adult eye and antenna of stalk-eyed fly develop from a complex eye-antennal imaginal disc. We analyzed the markers involved in proximo-distal (PD) axis of the developing eye imaginal disc of the stalk-eyed flies. We used homothorax (hth) and distalless (dll), two highly conserved genes as the marker for proximal and distal fate, respectively. We found that lateral extensions between eye and antennal field of the stalk-eyed fly's eye-antennal imaginal disc exhibit robust Hth expression. Hth marks the head specific fate in the eye-and proximal fate in the antenna-disc. Thus, the proximal fate marker Hth expression evolves in the stalk-eyed flies to generate lateral extensions for the placement of the eye on the head. Moreover, during pupal eye metamorphosis, the lateral extension folds back on itself to place the antenna inside and the adult compound eye on the distal tip. Interestingly, the compound eye in other insects does not have a prominent PD axis as observed in the stalk-eyed fly. K E Y W O R D S dacshund, distalless, Drosophila, eye development, eye-antennal imaginal disc, homothorax, proximo-distal axis, stalk-eyed fly

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Drosophila Eye Model to Study Neuroprotective Role of CREB Binding Protein (CBP) in Alzheimer’s Disease

Cited by 52 publications

References 85 publications

Ocular indicators of Alzheimer’s: exploring disease in the retina

Ocular indicators of Alzheimer’s: exploring disease in the retina

A Positive Feedback Loop of Hippo- and c-Jun-Amino-Terminal Kinase Signaling Pathways Regulates Amyloid-Beta-Mediated Neurodegeneration

Proximal fate marker homothorax marks the lateral extension of stalk‐eyed fly Cyrtodopsis whitei

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