Altered Amyloid Protein Processing in Platelets of Patients With Alzheimer Disease

Rosenberg, Roger N.; Baskin, Fred; Fosmire, Jennifer A; Risser, Richard C.; Adams, Perrie M.; Svetlik, Doris; Honig, Lawrence S.; Cullum, C. Munro; Weiner, Michael

doi:10.1001/archneur.1997.00550140019007

Cited by 121 publications

(99 citation statements)

References 27 publications

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“…Increased expression of APP, altered APP isoform ratios and processing patterns, and enhanced β-secretase activity are observed in platelets from patients with AD [60][61][62] , and these changes could result in overproduction of Aβ in the periphery. Blood levels of albumin, an Aβ carrier, are reduced in patients with AD 63 .…”

Section: Blood Abnormalitiesmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

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Section: Blood Abnormalitiesmentioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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“…This is supposedly an important mechanism leading to cerebral amyloid angiopathy in AD [16] . Early studies by Di Luca et al [17] and Rosenberg et al [18] showed a reduction in the ratio between larger (120 to 130 kDa) and smaller (110 kDa) specimens of sAPP in platelets of patients with AD. The so-called APP ratio was proposed as a method to ascertain the metabolic cleavage of APP in platelets, larger fragments corresponding to sAPP-α and smaller ones to sAPP-β.…”

Section: Amyloid-related Markers In Plateletsmentioning

confidence: 98%

“…Further studies from these groups and others have found interesting correlations between the APP ratio and other biological and clinical features of the disease. For instance, the presence of the APOE*4 allele is associated with a greater reduction in the APP ratio [18] . Positive correlations were observed between the APP ratio and cognitive performance [19] , both in clinical [20] and preclinical AD [21] .…”

Section: Amyloid-related Markers In Plateletsmentioning

confidence: 99%

Platelet biomarkers in Alzheimer’s disease

Talib

Joaquim²,

Forlenza³

2012

WJP

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The search for diagnostic and prognostic markers in Alzheimer's disease (AD) has been an area of active research in the last decades. Biochemical markers are correlates of intracerebral changes that can be identified in biological fluids, namely: peripheral blood (total blood, red and white blood cells, platelets, plasma and serum), saliva, urine and cerebrospinal fluid. An important feature of a biomarker is that it can be measured objectively and evaluated as (1) an indicator of disease mechanisms (markers of core pathogenic processes or the expression of downstream effects of these processes), or (2) biochemical responses to pharmacological or therapeutic intervention, which can be indicative of disease modification. Platelets have been used in neuropharmacological models since the mid-fifties, as they share several homeostatic functions with neurons, such as accumulation and release of neurotransmitters, responsiveness to variations in calcium concentration, and expression of membrane-bound compounds. Recent studies have shown that platelets also express several components related to the pathogenesis of AD, in particular to the amyloid cascade and the regulation of oxidative stress: thus they can be used in the search for biomarkers of the disease process. For instance, platelets are the most important source of circulating forms of the amyloid precursor protein and other important proteins such as Tau and glycogen synthase kinase-3B. Moreover, platelets express enzymes involved in membrane homeostasis (e.g., phospholipase A2), and markers of the inflammatory process and oxidative stress. In this review we summarize the available literature and discuss evidence concerning the potential use of platelet markers in AD.

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“…Several isoforms of AβPP exist due to alternative splicing, with AβPP695 predominately expressed in neurons. However, in sporadic AD (sAD), two reports reveal a ratio shift towards the neuronal expression of AβPP isoforms other than AβPP695 [31,32], and additional reports indicate alterations in AβPP expression in platelets of AD individuals [33][34][35]. In addition to alternative splicing, AβPP may be truncated on the carboxyl end to form smaller and less amyloidogenic fragments.…”

Section: Amyloid Cascade Hypothesis: Mechanisms and Therapeutics For mentioning

confidence: 99%

“…Though these may prove promising by halting the development of tau tangles and synaptic dysfunction, a major area of investigation left unstudied is whether the mitochondrial impairments caused by Aβ overproduction, aggregation, and accumulation are reversible. In addition, though currently available data shows some promise for secretase-inhibiting therapy, it is important to consider a report of immunotherapyassociated clearance of amyloid plaques without improvement in disease progression or survival [185], even though immune therapy was previously shown to reduce Aβ levels [33,[186][187][188][189]. Additionally, while the overexpression of neprilysin, an Aβ-degrading enzyme, reduces Aβ levels by 50%, it did not improve impairments in spatial learning and memory in transgenic mice [190].…”

Section: Disease-modifying Anti-alzheimer's Drugs (Dmaad) and Mitochomentioning

confidence: 99%

The Mitochondrial Secret(ase) of Alzheimer's Disease

Young

Bennett

2010

JAD

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Abstract. Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory and cognition and pathologically by extracellular amyloid-β (Aβ) deposits and intraneuronal aggregates of hyperphosphorylated tau. Since its proposal in 1992, the amyloid cascade hypothesis implicates Aβ overproduction as a causative event in disease pathogenesis, and this thinking has predominated the field's understanding of AD pathogenesis and the development of potential therapeutics (i.e., Aβ-reducing agents). Though Aβ has been shown to induce AD pathology, unanswered questions for sporadic AD development suggests this hypothesis is best applied to familial disease only. The more recent mitochondrial cascade hypothesis is supported by data showing that early impairments of mitochondrial dysfunction and oxidative stress may precede Aβ overproduction and deposition. However, the development of Aβ-reducing agents continues. Unfortunately, these agents have not been efficiently tested for their effect on one of the earliest AD pathologies, i.e., mitochondrial dysfunction. This paper will review supporting data for the amyloid and mitochondrial cascade hypotheses, reports of the effects of secretase inhibitors on AD-phenotypic cells and animals, and begin to look at a potential role for γ-secretase, which is localized to mitochondria, in AD-related mitochondrial dysfunction.

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Altered Amyloid Protein Processing in Platelets of Patients With Alzheimer Disease

Cited by 121 publications

References 27 publications

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

Platelet biomarkers in Alzheimer’s disease

The Mitochondrial Secret(ase) of Alzheimer's Disease

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