Amyloid and Neurodegeneration: Alzheimer's Disease and Retinal Degeneration

Prakasam, A.; Venugopal, Chitra; Anitha, S; Pacheco‐Quinto, Javier; Zhou, Yan; Pappolla, Miguel A.; Sharpe, K. A.; Lahiri, Debomoy K.; Greig, Nigel H.; Rohrer, Ba ̈rbel; Sambamurti, Kumar

doi:10.1007/978-0-387-30375-8_7

Cited by 3 publications

(4 citation statements)

References 227 publications

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“…Given that the ocular chambers are readily accessible, the eye may lead to a better understanding of the pathways leading to Aβ accumulation and aggregation in the CNS. Such studies may also explain some of the differences in the epidemiology of AD and AMD [7]. …”

Section: Discussionmentioning

confidence: 99%

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Differential Accumulation of Secreted AβPP Metabolites in Ocular Fluids1

Prakasam

Muthuswamy

Ablonczy

et al. 2010

JAD

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The Alzheimer amyloid-β (Aβ) accumulates in several types of retinal degeneration and in Alzheimer disease (AD), but its source has been unclear. We detected the neuronal 695 amino acid form of Aβ-precursor protein (AβPP) in the normal retina and AβPP751 in the retinal pigment epithelium (RPE) and anterior eye tissues. Similar to the brain, α- and β-secretases cleaved AβPP to soluble derivatives (sAPP) α or β and membrane-bound C-terminal fragments (CTF) α or β in the retina and RPE. Levels of sAPP were particularly high in the vitreous and low in aqueous humor revealing a molecular barrier for AβPP. In contrast, Aβ40 and Aβ42 levels were only 50% lower in the aqueous than the vitreous humor, indicating relatively barrier-free movement of Aβ. These studies demonstrated a relatively high yield of AβPP and Aβ in the ocular fluids, which may serve as a trackable marker for AD. In addition, failure of free clearance from the eye may trigger retina degeneration in a manner similar to Aβ-related neurodegeneration in AD.

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Section: Discussionmentioning

confidence: 99%

“…Aβ, a clinical biomarker in AD, is an integral component of drusen. Like senile plaques, drusen also contains deposits of apolipoprotein E (ApoE), a major risk factor for AD as well as AMD [7]. …”

Section: Introductionmentioning

confidence: 99%

Differential Accumulation of Secreted AβPP Metabolites in Ocular Fluids1

Prakasam

Muthuswamy

Ablonczy

et al. 2010

JAD

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“…Studies show that ApoE-ε4, which also promotes premature atherosclerosis, is significantly less frequent in centenarians than in controls, whereas the ApoE-ε2 allele that has been associated with type III and IV hyperlipidemia is significantly increased in this extremely long-lived group [54]. However, ApoE-ε4 as a risk factor in human disease is complex, as it appears to protect carriers against development of age-related macular degeneration, a condition that is associated with amyloid deposition in subretinal pigmented epithelium deposits known as drusen [55]. Several theories are built around ApoE-ε4, such as the failure of CNS cholesterol homeostasis, promoting plaque formation by chaperoning Aβ deposition, reduced Aβ degrading capacity, incorporation into plaques as fragments, promoting APP degradation affecting neuronal survival to ultimately cause AD-related neurodegeneration [56–58].…”

Section: Apoe and Selected Risk Factors Affecting Amyloidosismentioning

confidence: 99%

Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

Baranello¹,

Bharani²,

Padmaraju³

et al. 2015

CAR

261

196

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Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer’s disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin-2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβ turnover.

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“…However in relation to AD amyloid beta plaques find a common role in both AD and AMD due to its presence in both brain as well as drusen an extracellular deposit between retinal pigment epithelium and Bruch’s membrane. 37 – 39 For the last two decades the link between AMD and APOE has been a subject ofcontroversy. l. In 1998, a study linked theAPOE epsilon 2 variant with AMD at genetic level.…”

Section: Immunoreactivity Of Milk Metabolitesmentioning

confidence: 99%

Milk metabolites and neurodegeneration: Is there crosstalk?

Thakur

Anand

2015

ANS

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Milk has been considered as a natural source of nutrition for decades. Milk is known to be nutrient-rich which aids the growth and development of the human body. Milk contains both macro- and micronutrients. Breast milk is widely regarded as the optimal source of neonatal nutrition due to its composition of carbohydrates, proteins, minerals and antibodies. However, despite the wide use of milk products, investigations into the role of milk in degenerative diseases have been limited. This review will examine the relationship between the β-casein gene found in bovine milk and disease states by using age-related macular degeneration as an example.

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Amyloid and Neurodegeneration: Alzheimer's Disease and Retinal Degeneration

Cited by 3 publications

References 227 publications

Differential Accumulation of Secreted AβPP Metabolites in Ocular Fluids1

Differential Accumulation of Secreted AβPP Metabolites in Ocular Fluids1

Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease

Milk metabolites and neurodegeneration: Is there crosstalk?

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