MSc lecture_Farrell_October 2024

Down syndrome is caused by having three copies of chromosome 21 (Hsa21), a condition known as Trisomy 21.

1. Understand the genetic cause of Down syndrome; 2) Understand major effects on brain development and early onset Alzheimer's disease; 3) Understand how individual genes on chromosome 21 can be linked to neurobiological alterations.

Increased incidence of Alzheimer's disease, autism, epilepsy, autoimmune disorders, obstructive sleep apnea, heart disease, and pediatric leukemias.

Atrioventricular septal defect (AVSD) is especially common, occurring in about 50% of individuals with Down syndrome.

Hirschsprung disease, which is due to failure to fully innervate the colon (absence of ganglion cells).

The adjusted hazard ratio for death from COVID-19 in people with Down syndrome is 10.39 (95% CI 7.08–15.23) compared to those without a learning disability.

Patients with intellectual disabilities had lower rates of non-invasive respiratory support (12.3% vs 16.9%) and tracheal intubation (7.2% vs 11.2%) and spent less time in intensive care (11.7% vs 20.3%) compared to controls.

Delays include sitting alone (6–30 months vs typical 5–9 months), walking alone (1–4 years vs 9–18 months), first words (1–4 years vs 1–3 years), and two-word phrases (2–7.5 years vs 15–32 months).

Intellectual disability in Down syndrome typically ranges from mild to severe, around IQ 30–70.

Visuospatial memory tends to be a relative strength in individuals with Down syndrome.

Reduced total brain volume, simplified gyral pattern, enlarged ventricles, reduced frontal-temporal cortex area (with increased cortical thickness), reduced hippocampus, and reduced cerebellum.

Reduced neuronal production and neuron number, abnormal dendritic arborization and spine density, deficits in oligodendrocyte maturation and myelination, and alterations in microglia and astrocyte morphology and transcriptomes.

Intraneuronal amyloid depositions, extracellular diffuse amyloid plaques, neuritic plaques, cerebral amyloid angiopathy (CAA), and neurofibrillary tangles (NFTs).

Neuropathology progresses from intraneuronal amyloid early, to diffuse plaques, then neuritic plaques and NFTs, and eventually severe AD neuropathology and dementia, with many markers reaching high prevalence by mid-adulthood.

Microglia become activated, producing cytokines, chemokines, and reactive oxygen species; astrocytes become dysregulated, both contributing to neuronal dysfunction, synaptic loss, and a harmful brain environment.

Changes include increased ramified microglia early, increased microglial soma size from childhood/young adulthood, appearance of rod-like microglia in mid-adulthood, and dystrophic microglia later, along with transcriptomic signatures related to AD.

Three copies of Hsa21 modify microglial morphology and immune response, altering expression of genes such as SPP1, P2RY12, P2RY13, and CX3CR1, with ongoing work to determine mechanisms and consequences.

A = Amyloid, T = Tau, N = Neurodegeneration; these biomarkers are used to stage and diagnose AD in Down syndrome similarly to late-onset AD.

There is a very high incidence of adult-onset seizures in people with Down syndrome and Alzheimer's disease, approximately 75%.

The deck references a JAMA Neurology study showing vascular amyloid deposition patterns in brains of people with Down syndrome in the context of lecanemab investigation.

Chromosome 21 contains about 236 coding genes.

Dosage-sensitive genes are genes whose phenotypic effect is altered by gene copy number; their function is concentration-dependent and can fail homeostatic regulation when copy number changes.

Non-amyloidogenic processing: α-secretase then γ-secretase cleaves APP producing sAPPα, P3 and CTFα (no Aβ). Amyloidogenic processing: β-secretase then γ-secretase cleaves APP producing sAPPβ, Aβ peptide and CTFβ (C99), which leads to Aβ formation.

Cases with partial trisomy 21 that do not include the APP locus do not develop AD, and APP locus duplications cause autosomal dominant early-onset AD, implicating APP dose in AD risk.

Three copies of APP raise APP transcript and protein levels, increase APP C-terminal fragments (CTFβ) and Aβ (including Aβ42 and Aβ40), contributing to amyloid pathology.

Aβ42 and Aβ40 levels are increased in both soluble and insoluble extracellular fractions in AD-DS compared to controls, showing significantly raised Aβ peptide levels.

Mouse genomes have regions homologous to human chromosome 21 across Mmu10, Mmu17 and Mmu16, allowing segmental duplications or transgenic approaches to test gene-dose effects in vivo.

Ts65Dn is a mouse model carrying ~50% of Hsa21 orthologues in three copies (including App). It showed that 3 copies of App are necessary for cholinergic neuron degeneration and implicated APP-CTF/Aβ in pathology. [page 31–32]

Three copies of App are sufficient and necessary for early-onset AD in DS models; increased App raises APP and cleavage products; normalizing App gene dose rescues cholinergic neuron loss, although mouse App triplication alone didn't produce aggregated Aβ in early models.

Candidate modulatory genes include ST3 (STX?), BACE2, DYRK1A, and APOE polymorphisms may also influence AD risk and age of onset. p.34, 39

The Tc1 model carries a freely segregating human chromosome 21 with ~200 Hsa21 genes, but the human APP gene in Tc1 is not functional.

Crossing Tc1 with AppNL-F decreased Aβ plaque deposition compared to AppNL-F alone.

Next-gen models humanize the mouse Aβ sequence (and introduce familial AD mutations like Swedish or Beyreuther/Iberian) in the endogenous App locus to increase total Aβ1-x and Aβ1-42 and alter Aβ42/Aβ40 ratios.

Dp3Tyb crossed with AppNL-F decreased Aβ plaque deposition; candidate genes in the Dp3Tyb region include DYRK1A and BACE2.

Down syndrome is caused by an extra Hsa21 affecting all organs; it causes neurodevelopmental changes and early-onset AD primarily due to APP triplication, but many Hsa21 genes modulate phenotypes and mechanisms are complex and under active study. p.23, 43

1. Genetic cause: three copies of Hsa21 (~236 coding genes). 2) Major effects: mild–moderate ID, smaller specific brain regions, and early-onset AD driven by APP triplication with altered neuroimmune biology. 3) Individual genes on Hsa21 can be tested for sufficiency/necessity for DS phenotypes (e.g., APP is sufficient/necessary for EOAD). [page 42–44]