Tg-SwDI Transgenic Mice Exhibit Novel Alterations in AβPP Processing, Aβ Degradation, and Resilient Amyloid Angiopathy

Abstract

Alzheimer's disease (AD) is characterized by the accumulation of extracellular insoluble amyloid, primarily derived from polymerized amyloid-␤ (A␤) peptides. We characterized the chemical composition of the A␤ peptides deposited in the brain parenchyma and cerebrovascular walls of triple transgenic Tg-SwDI mice that produce a rapid and profuse A␤ accumulation. The processing of the N-and C-terminal regions of mutant A␤PP differs substantially from humans because the brain parenchyma accumulates numerous, diffuse, nonfibrillar plaques, whereas the thalamic microvessels harbor overwhelming amounts of compact, fibrillar, thioflavine-S-and apolipoprotein E-positive amyloid deposits. The abundant accretion of vascular amyloid, despite low A␤PP transgene expression levels, suggests that inefficient A␤ proteolysis because of conformational changes and dimerization may be key pathogenic factors in this animal model. The disruption of amyloid plaque cores by immunotherapy is accompanied by increased perivascular deposition in both humans and transgenic mice. This analogous susceptibility and response to the disruption of amyloid deposits suggests that Tg-SwDI mice provide an excellent model in which to study the functional aftermath of immunotherapeutic interventions. These mice might also reveal new avenues to promote amyloidogenic A␤PP processing and fundamental insights into the faulty degradation and clearance of A␤ in AD, pivotal issues in understanding AD pathophysiology and the assessment of new therapeutic agents. Alzheimer's disease (AD) dementia is affecting an escalating proportion of the elderly population because of a dramatic increase in life expectancy. This neurodegenerative disorder is characterized by the profuse accumulation of extracellular insoluble amyloid in cerebral vessels and senile plaques, which are mainly composed of amyloid fibrils derived from polymerized amyloid-␤ (A␤) peptides. Amyloid-␤40/42 peptides are generated from the proteolytic degradation of the amyloid-␤ precursor protein (A␤PP) by the action of the ␤-and ␥-secretases. Amyloid-␤ peptides are very insoluble and resistant to subsequent proteolytic degradation because they contain a segment of the hydrophobic transmembrane domain of A␤PP. The prominent amyloid buildup associated with AD has resulted in the amyloid cascade hypothesis in which amyloid plays a fundamental mechanistic role in the pathogenesis and the emergence of dementia. A second relevant lesion in the AD brain is the accumulation of neurofibrillary tangles and neuropil threads that are mainly composed of hyperphosphorylated tau, a microtubule-associated protein.To determine the mechanisms leading to amyloid deposition and its clearance as well as its pathophysiological effects on brain tissue, several transgenic (Tg) mice have been engineered that carry familial AD A␤PP mutations with suitable promoters to accelerate the deposition of A␤

Prolonged diet induced obesity has minimal effects towards brain pathology in mouse model of cerebral amyloid angiopathy: Implications for studying obesity–brain interactions in mice

“…The TgSwDI mouse was generated as described previously [29]. The CAA and corresponding control mice were maintained and genotyped as described previously [29–31,37]. Briefly, the transgenic mouse model expressed the human AβPP770 isoform including the Swedish, Dutch and Iowa mutations under the Thy-1 promoter.…”

“…No studies to date have examined the impact of DIO towards CAA. In the current study, we examined the effects of prolonged DIO towards multiple neuropathological processes in an established CAA mouse model [29–31]. …”

Chemical characterization of pro-inflammatory amyloid-beta peptides in human atherosclerotic lesions and platelets

“…Samples from the HPLC, representing the total fractionation runs, were assessed for the presence of Aβ40 and Aβ42 peptides (Invitrogen, Carlsbad CA) using Western blots as described before [47]. …”

Biochemical and Morphological Characterization of the AβPP/PS/Tau Triple Transgenic Mouse Model and Its Relevance to Sporadic Alzheimer's Disease

“…A detailed account of the protocol for Western blots (WB) is described elsewhere [20, 21]. Briefly, brain tissue was homogenized in RIPA buffer (Sigma), containing a PIC (Roche).…”