Table 5 Animal models of Lewy body dementia
Model | Amyloid pathology | Tau pathology | α-synuclein pathology | Synaptic deficit | Dopaminergic deficit | Widespread neurodegeneration | Cognitive impairment | Motor impairment | Potential Synergism | References |
|---|---|---|---|---|---|---|---|---|---|---|
hAPP/hSYN (hSYN line D x hAPP line J9) mice | Aβ deposition unchanged by synuclein | Not reported | Increased and more fibrillar (15%) αsyn accumulation over time | Loss of synaptophysin terminals (4–20 months) | Not reported | Cholinergic neurodegeneration (4–20 months) | Memory deficits driven by hAPP (6 months) | Motor deficits accelerated by hAPP (6 months) | Yes, Aβ enhances αsyn aggregation, neurodegeneration, and motor deficits | [213] |
DLB-AD (3xTg-AD x M83-h A53T syn) mice | Increased Aβ plaques (6–12 months) | Increased tau tangles (6–12 months) | Increased αsyn inclusions (6–12 months) | Significant synaptic loss (6–12 months) | Not reported | No difference in 3xTg vs. DLB-AD | Accelerated cognitive decline (6–12 months) | Not detected | Yes, synergistic interactions exacerbated all 3 pathologies | [3] |
APP/PS1 x [A30P] aSYN mice + αsyn PFF or ampLB | Reduced Aβ plaques 4–16 weeks | Not reported | Not detected | Not reported | Not reported | Not reported | Preserved cognitive function (up to 12 months) | Not reported | No, αsyn inhibited Aβ aggregation | [219] |
APP J20 x αsyn Tgl2.2 (APP/αsyn); APP/αsyn-KO mice | Reduced Aβ plaques with αsyn overproduction, increased Aβ with αsyn knockout (up to 12 months) | Increased MC1 & CP13 immunoreactivity in APP/αSyn mice (6 months) | Increased in αsyn oligomers in APP/αsyn mice (6 months) | Synaptic markers decreased in APP/αsyn mice (6 months) | TH + neuron loss in SNpc and VTA, 4.5 months 6mpi | Not reported | Worsened memory with αsyn overproduction; improved with knockout (6 months) | Not reported | No, bidirectional effects of αsyn and Aβ observed | [220] |
5xFAD mice + αsyn mPFF APP-KI mice + αsyn mPFFs | Increases in 1.5 months injected mice at 6mpi, increases in 4.5 months injected at 3 and 6mpi | neuritic at 3 mpi neuronal and neuritic at 6 mpi | Increase in brain-wide αsyn pathology from 3–6 mpi | dystrophic neurites | Not detected | NeuN + neuron loss in the hippocampus | Y maze by 3mpi | Motor deficits in rotarod 3 mpi | Yes, Aβ promotes seeding of αsyn and tau | [217] |
APP/PS1 L85 x h-αsyn M20 (M20/L85) mice + αsyn PFF | PFFs increase Aβ in APP mice but not αsyn/APP mice | Not reported | Aβ exacerbates αsyn pathology (2–4 months post-injection) | Not detected | Not reported | Not reported | Not reported | Not reported | Yes, Aβ exacerbates αsyn pathology in APP/αsyn mice, and αsyn PFFs exacerbate Aβ in APP mice | [218] |
hThy1-αsyn “Line 61” mice + AAV-tau; hTau mice + AAV-αsyn; APP/PS1 mice + AAV-αsyn | APP/PS1 pathology unaffected by AAV-αsyn production at 3 months post-injection (6 months) | hTau pathology mild/ unaffected by AAV-αsyn at 6 mpi (9 months) | Thy1-αsyn pathology mild and unaffected by AAV-tau expression 6 mpi (9 months) | Not reported | Not reported | Not reported | Motor and cognitive impairments in base animal models not affected by additional transgene delivery via AAV | Not reported | No, additional transgene delivery via AAV did not exacerbate any existing pathologies or behaviors | [221] |