Gene Expression Studies on Human Trisomy 21 iPSCs and Neurons: Towards Mechanisms Underlying Down’s Syndrome and Early Alzheimer’s Disease-Like Pathologies

Five patients with trisomy 21 (Down's syndrome (DS)), referred to us for evaluation of dementia, were instead found to have major depression. All had shown cognitive and behavioural deterioration and this had led to a mistaken diagnosis of Alzheimer's disease in two. We outline and contrast the features of major depression and Alzheimer's disease in DS, and suggest that electroconvulsive therapy is an effective treatment for major depression in DS.

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Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease

Nature Communications ◽

10.1038/s41467-021-22742-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Julie C. Lauterborn ◽

Pietro Scaduto ◽

Conor D. Cox ◽

Anton Schulmann ◽

Gary Lynch ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Down Syndrome ◽

Parietal Cortex ◽

Direct Evidence ◽

Synaptic Membranes ◽

Post Mortem ◽

Expression Studies ◽

Gene Expression Studies

AbstractSynaptic disturbances in excitatory to inhibitory (E/I) balance in forebrain circuits are thought to contribute to the progression of Alzheimer’s disease (AD) and dementia, although direct evidence for such imbalance in humans is lacking. We assessed anatomical and electrophysiological synaptic E/I ratios in post-mortem parietal cortex samples from middle-aged individuals with AD (early-onset) or Down syndrome (DS) by fluorescence deconvolution tomography and microtransplantation of synaptic membranes. Both approaches revealed significantly elevated E/I ratios for AD, but not DS, versus controls. Gene expression studies in an independent AD cohort also demonstrated elevated E/I ratios in individuals with AD as compared to controls. These findings provide evidence of a marked pro-excitatory perturbation of synaptic E/I balance in AD parietal cortex, a region within the default mode network that is overly active in the disorder, and support the hypothesis that E/I imbalances disrupt cognition-related shifts in cortical activity which contribute to the intellectual decline in AD.

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Down's Syndrome with Alzheimer's Disease-Like Pathology: What Can It Teach Us about the Amyloid Cascade Hypothesis?

International Journal of Alzheimer s Disease ◽

10.4061/2010/175818 ◽

2010 ◽

Vol 2010 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Rania M. Bakkar ◽

Guangju Luo ◽

Thomas A. Webb ◽

Keith A. Crutcher ◽

Gabrielle M. de Courten-Myers

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Trisomy 21 ◽

Down's Syndrome ◽

Down’S Syndrome ◽

Life Time ◽

Later Life ◽

Amyloid Cascade Hypothesis ◽

Significant Difference ◽

Amyloid Cascade

Down's syndrome (DS, trisomy 21) represents a complex genetic abnormality that leads to pathology in later life that is similar to Alzheimer's disease (AD). We compared two cases of DS with APOE 3/3 genotypes, a similar age at death, and comparable amyloid-beta 42 peptide (A42) burdens in the brain but that differed markedly in the severity of AD-like pathology. One exhibited extensive neurofibrillary pathology whereas the other showed minimal features of this type. Comparable loads of A42 could relate to the cases' similar life-time accumulation of A due to trisomy 21-enhanced metabolism of amyloid precursor protein (APP). The cases' significant difference in AD-like pathology, however, suggests that parenchymal deposition of A42, even when extensive, may not inevitably trigger AD-like tau pathology (though it may be necessary). Thus, these observations of a natural experiment may contribute to understanding the nuances of the amyloid cascade hypothesis of AD pathogenesis.

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Detection of Lewy Bodies in Trisomy 21 (Down's Syndrome)

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100047405 ◽

1993 ◽

Vol 20 (1) ◽

pp. 48-51 ◽

Cited By ~ 31

Author(s):

Ravi Raghavan ◽

Clare Khin-Nu ◽

Andrew Brown ◽

Dorothy Irving ◽

Paul G. Ince ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Trisomy 21 ◽

Down's Syndrome ◽

Lewy Bodies ◽

Down’S Syndrome ◽

Alzheimer Type

ABSTRACT:The presence of cortical senile plaques and neurofibrillary tangles sufficient to warrant a neuropatho-logical diagnosis of Alzheimer's disease is well established in middle-aged individuals with Trisomy 21 (Down's syndrome). In contrast a relationship between Down's syndrome and Lewy bodies, one of the major neuropathological features of Parkinson's disease, has not been previously reported. In a cliniconeuropathological survey of 23 cases of Down's Syndrome, two patients, aged 50 and 56 years respectively, were found to have Lewy body formation in the substantia nigra in addition to cortical Alzheimer-type pathology. Neither case showed significant substantia nigra neuron loss although locus coeruleus loss was present in both. Since substantia nigra Lewy bodies are a characteristic neu-rohistological feature of idiopathic Parkinson's disease, their occurrence in cases of Down's syndrome with evidence of Alzheimer-type pathology supports an aetiopathological connection between Parkinson's disease, Alzheimer's disease, and Down's syndrome; and suggests that common pathogenic mechanisms may underlie aspects of neuronal degeneration in these three disorders, some of which may relate to aberrant chromosome 21 expression.

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