Phases of Aβ-deposition in the human brain and its relevance for the development of AD

Thal, Dietmar Rudolf; Rüb, Udo; Orantes, M; Braak, Heiko

doi:10.1212/wnl.58.12.1791

Cited by 2,785 publications

(2,607 citation statements)

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“…In postmortem studies, amyloid deposits were detected in the hypothalamus only in late phases of AD. 70 All A␤ plaques identified in the hypothalamus were of the Congo Red-negative amorphic type 71,72 and were comparable to the morphology of amyloid deposits observed in hippocampal and cortical structures more precociously in AD patients, 73 suggesting that different protective mechanisms are involved in the hypothalamus.…”

Section: Discussionmentioning

confidence: 72%

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Zussy

Brureau

Delair

et al. 2011

The American Journal of Pathology

121

129

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Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid ␤ protein (A␤) formed by pathological processing of the A␤ precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated A␤ fragment 25-35 (A␤ 25-35 ) in rats. Using a combined biochemical, behavioral, and morphological approach, we analyzed the peptide effects after 1, 2, and 3 weeks in the hippocampus, cortex, amygdala, and hypothalamus. The scrambled A␤ 25-35 peptide was used as negative control. The aggregated forms of A␤ peptides were first characterized using electron microscopy, infrared spectroscopy, and Congo Red staining. Intracerebroventricular injection of A␤ 25-35 decreased body weight, induced short-and long-term memory impairments, increased endocrine stress, cerebral oxidative and cellular stress, neuroinflammation, and neuroprotective reactions, and modified endogenous amyloid processing, with specific time-course and regional responses. Moreover, A␤ 25-35 , the presence of which was shown in the different brain structures and over 3 weeks, provoked a rapid glial activation, acetylcholine homeostasis perturbation, and hippocampal morphological alterations. Alzheimer's disease (AD) is a chronic neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss in brain areas responsible for learning and memory impairments. 1 The major component of senile plaques is an amyloid ␤ protein (A␤) derived from amyloid precursor protein (APP). Genetic, cell biological, and postmortem studies on AD brain, together with A␤ neurotoxicity findings, gave rise to the amyloid cascade hypothesis to explain A␤-associated neurodegenerative processes. 2 In normal healthy individuals, A␤ peptides are present only in small quantities, as soluble monomers that circulate in cerebrospinal fluid and blood. In AD patients, A␤ peptides, which vary in length from 40 to 43 amino acids, accumulate as insoluble fibrillar deposits. 3 When cultured rat hippocampal neurons are exposed to aggregated A␤ peptides, their neurites adopt a dystrophic appearance and become comparable to those observed surrounding and infiltrating senile plaques. This observation suggested that A␤ is responsible for the neuritic abnormalities in AD pathology. 4 Structure-activity studies revealed that peptides containing the highly hydrophobic 25-35 region formed stable aggregates and mediated neuronal death by necrosis or apoptosis. 5,6,7 The truncated A␤ 25-35 fragment includes extracellular and intramembrane residues that have been reported to represent an active region of A␤. 8

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Section: Discussionmentioning

confidence: 72%

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Zussy

Brureau

Delair

et al. 2011

The American Journal of Pathology

121

129

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“…78,79 However, considered together with the early appearance of Ab relative to p-tau, the marked increase in p-tau in individual Ab-positive synapses is consistent with a hypothesis that p-tau induction is directly driven by synaptic oAb; synaptic p-tau may then lead to anterograde and retrograde trans-synaptic spread of tau pathology. Such a hypothesis is supported by the following multiple lines of evidence: i) the exclusive initial appearance of Ab in the neocortex before dementia onset, which has extensive reciprocal projections with hippocampus and entorhinal cortex 48,80 ; ii) the well-established regional propagation of tau pathology in human disease and animal models 79,81e83 ; iii) the observation that low…”

Section: Discussionmentioning

confidence: 99%

“…46 As previously reported, synaptic terminals from control cases show little to no Ab immunolabeling ( Figure 1C) 26,33,42,47 ; representative plots from AD cases illustrate the rise in synaptic Ab with increasing neuropathologic disease stage and the degree to which synaptic terminal Ab increases between plaque stage 0 (no plaque deposition) and stage C (end-stage plaque deposition) (Figure 1, D and E). 48 Figure 2A shows group differences in aggregate flow cytometric data [F(3,30) Z 6.13, P Z 0.002] in both early-stage (Braak II to IV) and late-stage (Braak V to VI) AD cases. Total in situ Ab level was increased above the control and HPC groups (P< 0.05), which were not different from each other.…”

Section: Amyloid-b Precedes P-tau In Ad Synapsesmentioning

confidence: 99%

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Bilousova

Miller

Poon

et al. 2016

The American Journal of Pathology

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Amyloid-b (Ab) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Ab and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Ab and p-tau in large populations of individual synaptic terminals. Soluble Ab oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Ab was elevated in patients with early-and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Ab oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Ab-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Ab drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed. (Am J Pathol 2016, 186: 185e198; http://dx.doi.org/10.1016/j.ajpath.2015 A large body of evidence indicates that soluble oligomers of amyloid-b (Ab) are the primary toxic peptides that initiate downstream tau pathology in the amyloid cascade hypothesis of Alzheimer disease (AD). 1,2 However, the time course and severity of AD dementia have been generally found to correlate with neurofibrillary tangle development rather than plaque appearance, 3e8 although a few studies have linked plaques with early cognitive decline. 9e12 Soluble oligomeric

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“…Neuropathologic diagnosis was made using previously published neuropathologic criteria, including Braak stages,18, 19 Consortium to Establish a Registry for Alzheimer's Disease scores,19, 20 Thal A β phases,19, 21 LBD pathologic criteria,11 and FTLD classification22 by neuropathologists who were blinded to the 123 I‐FP‐CIT SPECT findings.…”

Section: Methodsmentioning

confidence: 99%

Clinicopathological and ¹²³I‐FP‐CIT SPECT correlations in patients with dementia

Jung

Jordan

Lowe

et al. 2018

Ann Clin Transl Neurol

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The relationship between clinicopathologic diagnosis and 123I‐FP‐CIT SPECT in 18 patients with dementia (12 with Lewy body disease) from one center in the United States was assessed. The sensitivity and specificity of abnormal 123I‐FP‐CIT SPECT with reduced striatal uptake on visual inspection for predicting Lewy body disease were 91.7% and 83.3%, respectively. The mean calculated putamen to occipital ratio (mPOR) based on regions of interest was significantly reduced in Lewy body disease compared to non‐Lewy body disease cases (P = 0.002). In this study, abnormal 123I‐FP‐CIT SPECT was strongly associated with underlying Lewy body disease pathology, supporting the utility of 123I‐FP‐CIT SPECT in the clinical diagnosis of dementia with Lewy bodies.

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Phases of Aβ-deposition in the human brain and its relevance for the development of AD

Cited by 2,785 publications

References 48 publications

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Clinicopathological and ¹²³I‐FP‐CIT SPECT correlations in patients with dementia

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Phases of Aβ-deposition in the human brain and its relevance for the development of AD

Cited by 2,785 publications

References 48 publications

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Clinicopathological and 123I‐FP‐CIT SPECT correlations in patients with dementia

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Product

Resources

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Clinicopathological and ¹²³I‐FP‐CIT SPECT correlations in patients with dementia