P1-195 Oligomerization of Alzheimer's Aβ within processes and synapses of cultured neurons and brain

Takahashi, Riku; Almeida, Cláudia G.; Kearney, Patrick F.; Yu, Fangmin; Lin, Michael; Milner, Teresa A.; Gouras, Gunnar K.

doi:10.1016/s0197-4580(04)80508-6

Cited by 7 publications

(8 citation statements)

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“…Taken together, these authors concluded that Aβ oligomerization begins intraneuronally [17]. More recently, Gouras and his colleagues have demonstrated that Aβ42 aggregates into oligomers within endosomal vesicles and along microtubules of neuronal processes, both in neurons isolated from transgenic mice and in the human AD brain [18]. Other groups have also shown that intracellular Aβ and oligomers can accumulate following treatment with metal and thiol inhibitors or chloroquine treatment, whereas fucoidan, a scavenger receptor antagonist, may decrease multimer accumulation [19,20].…”

Section: Intracellular Aβ In Alzheimer's Diseasementioning

confidence: 95%

Amyloid β-Peptide: The Inside Story

Tseng

Kitazawa²,

LaFerla³

2004

CAR

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The amyloid beta-peptide (Abeta) plays an early and critical role in the pathogenic cascade leading to Alzheimer's disease (AD). Abeta is typically found in extracellular amyloid plaques that occur in specific brain regions in the AD and Down syndrome brain. Mounting evidence, however, indicates that intraneuronal accumulation of this peptide may also contribute to the cascade of neurodegenerative events that occur in AD and Down syndrome. A pathogenic role for intracellular Abeta is not without precedent, as it is known to be an early and integral component of the human muscle disorder inclusion body myositis (IBM). Therefore, it is plausible that intracellular Abeta may likewise induce cytopathic effects in the CNS, causing neuronal and synaptic dysfunction and perhaps even neuronal loss. Here we review recent evidence supporting a pathogenic role for intracellular Abeta in AD, Down syndrome, and IBM.

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Section: Intracellular Aβ In Alzheimer's Diseasementioning

confidence: 95%

Amyloid β-Peptide: The Inside Story

Tseng

Kitazawa²,

LaFerla³

2004

CAR

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“…Aliquots were titrated by adding 10 mM TBS buffer (pH 7.5) to achieve a final protein concentration of 1 g/1 l. Ten-microliter samples, in an equal volume of sample buffer, were subjected to overnight electrophoresis on 12.5% SDSpolyacrylamide Tris-tricine gels under nonreducing conditions. A␤ oligomers were detected by using oligomer-specific A11 polyclonal antibody (Biosource, Camarillo, CA) (23). Autoradiograms were scanned and converted into eight-bit grayscale digital files.…”

Section: Methodsmentioning

confidence: 99%

“…5a). In addition, the level of A␤ oligomers in the brain homogenate was assessed by nonreducing, SDS/PAGE using the A11 oligomerspecific antibody (23,24). No differences were found between A␤12-28P-and vehicle-treated Tg mice, and no oligomers were detected in WT animals ( Fig.…”

Section: Treatment Of Tg Mice With A␤12-28p: Monitoring the Immune Rementioning

confidence: 99%

Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease

Sadowski¹,

Pankiewicz²,

Scholtzova³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

150

149

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The amyloid-␤ (A␤) cascade hypothesis of Alzheimer's disease (AD) maintains that accumulation of A␤ peptide constitutes a critical event in the early disease pathogenesis. The direct binding between A␤ and apolipoprotein E (apoE) is an important factor implicated in both A␤ clearance and its deposition in the brain's parenchyma and the walls of meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the effect of blocking the apoE/A␤ interaction in vivo as a potential novel therapeutic target for AD pharmacotherapy, we have developed A␤12-28P, which is a blood-brain-barrier-permeable nontoxic, and nonfibrillogenic synthetic peptide homologous to the apoE binding site on the full-length A␤. A␤12-28P binds with high affinity to apoE, preventing its binding to A␤, but has no direct effect on A␤ aggregation. A␤12-28P shows a strong pharmacological effect in vivo. Its systemic administration resulted in a significant reduction of A␤ plaques and cerebral amyloid angiopathy burden and a reduction of the total brain level of A␤ in two AD transgenic mice models. The treatment did not affect the levels of soluble A␤ fraction or A␤ oligomers, indicating that inhibition of the apoE/A␤ interaction in vivo has a net effect of increasing A␤ clearance over deposition and at the same time does not create conditions favoring formation of toxic oligomers. Furthermore, behavioral studies demonstrated that treatment with A␤12-28P prevents a memory deficit in transgenic animals. These findings provide evidence of another therapeutic approach for AD.Alzheimer's pathology ͉ memory loss prevention ͉ peptide ͉ transgenic mice ͉ treatment A lzheimer's disease (AD) is the most common neurodegenerative disease worldwide, characterized by a progressive dysfunction in multiple cognitive domains and complex neuropathological features that include accumulation of amyloid-␤ (A␤) followed by synaptic dysfunction, formation of neurofibrillary tangles, and neuronal loss. With the expected increase in AD prevalence, as a function of the population aging, effective treatment for AD is critically needed. Multiple lines of evidence indicate that a disturbance of A␤ homeostasis is a paramount event in early disease pathogenesis (1). A␤ is a hydrophobic 39-to 43-aa peptide, which is derived from cleavage of a larger, synaptic transmembrane protein, the amyloid precursor protein (APP) (2). The accumulation of A␤ in the brain is determined by the rate of its generation versus in situ proteolytic degradation and clearance across the blood-brain-barrier [BBB; for review see Tanzi et al. (3)]. In the setting of increased concentration, A␤ monomers assemble into oligomers and fibrils and eventually become deposited, forming parenchymal plaques and cerebral amyloid angiopathy (CAA).Inheritance of the apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor identified so far. ApoE isotype inheritance modulates the prevalence, age of onset, and the burden of pathology in sporadic AD (4, 5). ApoE binds A␤ with high affinity a...

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“…However, it was recently noted that anti-A 42 endspecific antibodies stain lots of neurons in AD [20,26,27] and Down syndrome (DS) brains [28,29]. Further rigorous immunocytochemical studies revealed that intracellular A 42 is present in multivesicular bodies, and is associated with synaptic pathology in AD brain [30,31]. Moreover, an improved immunostaining method with autoclave pretreatment revealed A 42 accumulation in the cytosol, and even in the nucleus in AD and mutant APP-transgenic mice neurons [24].…”

Section: Abnormal a 42 Localization In The Cyto-sol And The Nucleus Omentioning

confidence: 99%

“…Findings that A 42 accumulates in synapses in AD brains [30,31] and in triple transgenic mouse (3x-Tg) [54] brains, might indicate a pathological role for A at this stage, but molecular mechanisms of synaptic damage remain to be elucidated. As extracellular A oligomers also induce synaptic dysfunction [55] through affecting calcium homeostasis [56], synapses may be damaged by both intracellular and extracellular A .…”

Section: Other Molecules Related To Intracel-lular a 42 Pathogenesismentioning

confidence: 99%

Intracellular Amyloid β-Protein and Its Associated Molecules in the Pathogenesis of Alzheimers Disease

Ohyagi

Tabira²

2006

MRMC

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Amyloid beta-protein (Abeta) plays a pivotal role in Alzheimer's disease (AD). Therapeutic strategies inhibiting Abeta aggregation and promoting extracellular Abeta removal are currently advocated. Here, we review recent literature on intracellular Abeta, especially intranuclear Abeta, and its associated molecules. We also discuss alternative therapeutic strategies to inhibit intracellular Abeta-related pathogenesis.

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P1-195 Oligomerization of Alzheimer's Aβ within processes and synapses of cultured neurons and brain

Cited by 7 publications

References 0 publications

Amyloid β-Peptide: The Inside Story

Amyloid β-Peptide: The Inside Story

Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease

Intracellular Amyloid β-Protein and Its Associated Molecules in the Pathogenesis of Alzheimers Disease

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P1-195 Oligomerization of Alzheimer's Aβ within processes and synapses of cultured neurons and brain

Cited by 7 publications

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Amyloid &#946;-Peptide: The Inside Story

Amyloid &#946;-Peptide: The Inside Story

Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease

Intracellular Amyloid &#946;-Protein and Its Associated Molecules in the Pathogenesis of Alzheimers Disease

Contact Info

Product

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Amyloid β-Peptide: The Inside Story

Amyloid β-Peptide: The Inside Story

Intracellular Amyloid β-Protein and Its Associated Molecules in the Pathogenesis of Alzheimers Disease