Suppression of Amyloid Deposition Leads to Long-Term Reductions in Alzheimer's Pathologies in Tg2576 Mice

Abstract

In amyloid precursor protein (APP) models of amyloid deposition, the amount of amyloid deposits increase with mouse age. At a first approximation, the extent of amyloid accumulation may either reflect small excesses of production over clearance that accumulate over time or, alternatively, indicate a steady-state equilibrium at that age, reflecting the instantaneous excess of production over clearance, which increases as the organism ages. To discriminate between these options, we reversibly suppressed amyloid deposition in Tg2576 mice with the anti-A␤ antibody 2H6, starting at 8 months, just before the first histological deposits can be discerned. Six months later, we stopped the suppression and monitored the progression of amyloid accumulation in control APP mice and suppressed APP mice over the next 3 months. The accumulation hypothesis would predict that the rate of amyloid from 14 to 17 months would be similar in the suppressed and control mice, while the equilibrium hypothesis would predict that the increase would be faster in the suppressed group, possibly catching up completely with the control mice. The results strongly support the accumulation hypothesis, with no evidence of the suppressed mice catching up with the control mice as predicted by equilibrium models. If anything, there was a slower rate of increase in the suppressed APP mice than the control mice, suggesting that a slow seeding mechanism likely precedes a rapid fibrillogenesis in determining the extent of amyloid deposition.

1α,25-Dihydroxyvitamin D3Reduces Cerebral Amyloid-β Accumulation and Improves Cognition in Mouse Models of Alzheimer's Disease

“…We show that, whereas Vdr increases Mdr1a and P-gp expression, which reduces brain A␤ levels, inhibition of P-gp function with elacridar leads to accumulation of soluble A␤ in the brain. Vdr activation during the period of plaque formation decreases the soluble hA␤ load and reduces plaque formation in younger TgCRND8 mice, improving conditioned fear memory, confirming that decreasing cerebral hA␤ load in these younger mice delays the progression and intensity of AD-like symptoms, as found by others in Tg2576 mice (Karlnoski et al, 2009). Shortterm treatment of older TgCRND8 mice after the period of plaque formation lowered the soluble hA␤ but was unable to decrease the plaque burden (Table 1).…”

“…A␤ peptides are formed by cleavage of the amyloid precursor protein (APP) via ␤-and ␥-secretases (Kang et al, 1987;Haass et al, 1992;Hartmann et al, 1997;Weidemann et al, 1999). The comparatively more hydrophobic 42 aa variant, A␤ , displays a greater tendency to form oligomers and insoluble plaques (Jarrett et al, 1993) and is considered to be more pathogenic (Roher et al, 1993;Lesné et al, 2006) compared with the 40 aa variant, A␤ 1-40 , a major component of cerebrovascular plaques (Miller et al, 1993).…”

Restoring Blood-Brain Barrier P-Glycoprotein Reduces Brain Amyloid-β in a Mouse Model of Alzheimer's Disease

“…Finally, although brain accumulation of A␤ is not the only major contributor to cognitive impairment in AD (Iadecola, 2004;Blennow et al, 2006), reducing A␤ accumulation in the transgenic hAPP (Tg2576) mouse model does delay pathology (Karlnoski et al, 2009). It remains to be seen to what extent a general, long-term strategy of targeting signals that upregulate blood-brain barrier P-glycoprotein will reduce brain A␤ burden over the long term and thus prove to be a useful therapeutic strategy for delaying the onset of AD and slowing the progression of the disease.…”

Quantitative Pharmacokinetic/Pharmacodynamic Analyses Suggest That the 129/SVE Mouse Is a Suitable Preclinical Pharmacology Model for Identifying Small-Molecule γ-Secretase Inhibitors

“…Disease-modifying drugs slowing AD progression are in urgent need, but they are still unavailable. One of the main hypotheses of AD etiology is the amyloid cascade hypothesis, which, based on multiple lines of strong evidence (Hardy and Higgins, 1992;Iversen et al, 1995;Shastry, 1998;Luo et al, 2001;Li et al, 2007;Karlnoski et al, 2009), postulates that AD is caused by abnormal accumulation and deposition of amyloid ␤ (A␤) in the brain. A␤ is generated through cleavage of the amyloid precursor protein (APP) first by ␤-secretase and then by ␥-secretase.…”