Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease

Abstract

Familial Danish dementia (FDD) is a progressive neurodegenerative disease with cerebral deposition of Dan-amyloid (ADan), neuroinflammation, and neurofibrillary tangles, hallmark characteristics remarkably similar to those in Alzheimer's disease (AD). We have generated transgenic (tg) mouse models of familial Danish dementia that exhibit the age-dependent deposition of ADan throughout the brain with associated amyloid angiopathy, microhemorrhage, neuritic dystrophy, and neuroinflammation. Tg mice are impaired in the Morris water maze and exhibit increased anxiety in the open field. When crossed with TauP301S tg mice, ADan accumulation promotes neurofibrillary lesions, in all aspects similar to the Tau lesions observed in crosses between β-amyloid (Aβ)-depositing tg mice and TauP301S tg mice. Although these observations argue for shared mechanisms of downstream pathophysiology for the sequence-unrelated ADan and Aβ peptides, the lack of codeposition of the two peptides in crosses between ADan-and Aβ-depositing mice points also to distinguishing properties of the peptides. Our results support the concept of the amyloid hypothesis for AD and related dementias, and suggest that different proteins prone to amyloid formation can drive strikingly similar pathogenic pathways in the brain.ADan | ABeta | tau | neurodegeneration | mouse model

Brain homogenates from human tauopathies induce tau inclusions in mouse brain

“…The amyloid cascade hypothesis of AD pathogenesis posits that the aggregation of Aβ triggers the formation of tau inclusions (39). Consistent with this view, previous work has demonstrated an interaction between Aβ and tau pathologies in some brain regions (40)(41)(42)(43)(44). However, in these studies, both APP and tau were mutant, unlike what is the case in AD, where tau is wild type (1).…”

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

“…Crossing mice transgenic for human mutant amyloid precursor protein with mice transgenic for human mutant tau results in increased tau deposition in some brain regions . Similarly, in mice transgenic for the Danish mutant form of human BRI2 and mutant tau, the extracellular deposition of Dan-amyloid promotes tau phosphorylation and aggregation (Coomaraswamy et al 2010). Phosphorylation of tau by GSK3b and AMPactivated protein kinase is a potential mechanism.…”

Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits

“…More recently, another FDD transgenic model with ADan deposition (called ADanPP-Tg mice) has been described (4). ADanPP-Tg mice do not show cognitive and memory defects in the first 12 mo of life despite considerable amyloid load.…”

“…ADanPP-Tg mice do not show cognitive and memory defects in the first 12 mo of life despite considerable amyloid load. At an older age, ADanPP-Tg mice show deficits with the cue navigation task of the Morris water maze associated with an increase of thigmotaxis and passive floating, lower speed, less body weight, and an anxiety-related phenotype (4). Thus, although the ADan peptide is believed to cause Danish dementia, the absence of memory deficits despite massive ADan peptide production and deposition in ADanPP-Tg mice is inconsistent with the amyloid cascade pathogenic hypothesis and suggests that other mechanisms cause memory loss in Danish patients.…”