a(HBP:HBP00018)
A similar outcome was observed in J20 transgenic mice after a total of three months of meningeal lymphatic ablation (Extended Data Fig. 9f); amyloid-β aggregates had formed in the meninges (Extended Data Fig. 9g) and the amyloid-β plaque load in the hippocampi of these mice was significantly increased (Extended Data Fig. 9h–k) PubMed:30046111
Extracellular deposition of amyloid-β aggregates, the main constituent of senile plaques, is considered to be a pathological hallmark of Alzheimer’s disease that contributes to neuronal dysfunction and behavioural changes PubMed:30046111
Overexpression of Mint1, Mint2, or Fe65 causes reduction in Aβ generation and deposition in the brains of transgenic mice, strongly suggesting a physiological role for these adaptors in regulating APP processing in the nervous tis- sue (17). PubMed:18650430
Overexpression of Mint1, Mint2, or Fe65 causes reduction in Aβ generation and deposition in the brains of transgenic mice, strongly suggesting a physiological role for these adaptors in regulating APP processing in the nervous tis- sue (17). PubMed:18650430
Overexpression of Mint1, Mint2, or Fe65 causes reduction in Aβ generation and deposition in the brains of transgenic mice, strongly suggesting a physiological role for these adaptors in regulating APP processing in the nervous tis- sue (17). PubMed:18650430
As DS also results in Abeta accumulation, the genes location suggests a link between BACE2 and APP processing PubMed:21214928
gamma-Secretase further cleaves C99 to release AICD and the amyloidogenic Abeta peptide which aggregates and fibrillates to form amyloid plaques in the brain PubMed:22122372
The amyloid plaques associated with AD were first purified and found to consist of multimeric aggregates of Abeta polypeptide containing about 40 amino acid residues in the mid-1980s (Glenner and Wong 1984; Masters et al. 1985) PubMed:22122372
Significantly, a 4-month treatment of Tg2576 mice with GW3965 reduced plaque deposition by > 50% and improved contextual memory in these animals [13]. PubMed:21718217
In a study reported by Kalinin et al., treatment of 5xFAD mice with the PPAR-d agonist, GW742, resulted in decreased plaque burden and an increase in the expression of two Ab proteases, neprilysin and IDE [72]. PubMed:21718217
Treatment of 5-month-old APP/PS1 mice for 8 weeks with ATRA (20 mg/kg/day) resulted in significant decreases in Ab deposition and tau phosphorylation in these mice. Additionally, it attenuated memory deficits seen in the Morris water maze [77]. PubMed:21718217
Bexarotene is a highly specific RXR agonist and is currently FDA approved with a favorable side effect profile. Studies in our laboratory have shown that treatment of APP/ PS1 animals with bexarotene for only 3 days results in a dramatic induction of ApoE and ABCA1 and the rapid reversal of AD-associated pathological hallmarks including reduction in amyloid deposition and deficits in behavior as well as neural networks. PubMed:21718217
When a higher dose of pioglitazone (7 days/40 mg/kg/day) was used in 10-monthold transgenic mice overexpressing the APP V717I mutation, a 20-- 25% decrease in plaque burden was observed with significant reduction in Ab42 levels within the brains of these animals [61]. PubMed:21718217
Furthermore, the treatment of APP/PS1 mouse model of AD with pioglitazone (80 mg/kg/day) for 9 days lowered plaque burden by ~ 50% and reversed behavioral deficits in contextual fear conditioning assay. PubMed:21718217
Pedersen and Flynn examined the effects of rosiglitazone and found that activation of PPAR-g ameliorated behavioral deficits in the Tg2576 AD mouse model. However, these animals displayed no changes in plaque pathology, but had reduced brain Ab42 levels. PubMed:21718217
These animals were treated with a low dose of rosiglitazone (3 mg/kg/ day) for 12 weeks and evaluated for plaque deposition and behavior. These animals displayed an approximate 50% decrease in amyloid deposition, a decrease in Ab oligomers, preservation of pre and postsynaptic proteins and the attenuation of cognitive deficits in the Morris water maze. PubMed:21718217
Mice expressing the ApoE4 isoform exhibited higher levels of Ab deposition in comparison to ApoE3 or ApoE2 expressing animals [36]. PubMed:21718217
The loss of abca1 resulted in not only the reduction of ApoE levels but also a paradoxical increase in Ab deposition in the brain parenchyma of these animals owing to enhanced deposition of poorly lipidated ApoE in the brain [50-52]. PubMed:21718217
AD is a chronic neurodegenerative disease characterized by the progressive deposition of the amyloid b (Ab) in the parenchyma of the brain. PubMed:21718217
Another important event that associates well with the Alzheimer disease pathology is the aggregation of the β-amyloid peptide [53]. This peptide interacts with α7 AChRs and has been reported to affect the nor- mal functioning of the latter, causing reduced neuronal survival [146,192–194]. PubMed:22040696
Epigallocatechin-3-gallate (EGCG), a small molecule that been shown to inhibit the aggregation of several amyloidogenic proteins such as a-syn, amyloid-beta and huntingtin [9, 37, 38, 105] binds to unfolded native amyloid-beta and a-syn and promotes the formation of nontoxic oligomers that do not convert into amyloid fibrils [37]. PubMed:28803412
In vitro studies have shown that curcumin inhibited the formation of fibrils and disaggregated amyloid-beta and a-syn [112, 114, 155]. PubMed:28803412
It also proved effective in cellu- lar models of PD, HD and AD 121,122 , as well as in mouse models of HD, AD and tauopathies, where it cleared aggregates, reduced neurodegeneration and ameliorated motor and cognitive performance 123–125 . PubMed:30116051
Moreover, the flavonol fisetin stimulated auto- phagic degradation of phosphorylated tau in cortical neu- rons via mTORC1-dependent activation of TFEB and the cytoprotective transcription factor nuclear factor eryth- roid 2-related factor 2 (NFE2L2) 149 . Fisetin also reduced Aβ accumulation in an APP/PS1 mouse model of AD 150 . PubMed:30116051
Structures of Aβ-aggregation inhibitors evaluated in current or past clinical trials. PubMed:23484434
Furthermore, expression of progranulin in the hippocampus of AD mice reduces the density of amyloid plaques by enhanc- ing the activity of neprilysin 281 . PubMed:30116051
Aβ42 and amylin (a pancreas-derived, AD-associated protein found in brain) are substrates for degradation by IDE, which also irreversibly traps Aβ42 and α-synuclein, preventing their aggregation and promoting ALN and UPS elimination 259 . PubMed:30116051
Indeed, TFEB over- expression reduced amyloid plaques in a APP/PS1 mouse model 148 . PubMed:30116051
Structures of Aβ-aggregation inhibitors evaluated in current or past clinical trials. PubMed:23484434
Structures of Aβ-aggregation inhibitors evaluated in current or past clinical trials. PubMed:23484434
Structures of Aβ-aggregation inhibitors evaluated in current or past clinical trials. PubMed:23484434
Representative examples of N-phenylamine Tau aggregation inhibitors and structural overlap with the Aβ40 aggregation inhibitor 33 or the nonsteroidal anti-inflammatory drug 34. PubMed:23484434
Structures of Aβ-aggregation inhibitors evaluated in current or past clinical trials. PubMed:23484434
Representative examples of N-phenylamine Tau aggregation inhibitors and structural overlap with the Aβ40 aggregation inhibitor 33 or the nonsteroidal anti-inflammatory drug 34. PubMed:23484434
Structures of Aβ-aggregation inhibitors evaluated in current or past clinical trials. PubMed:23484434
Extracellular deposition of amyloid-β aggregates, the main constituent of senile plaques, is considered to be a pathological hallmark of Alzheimer’s disease that contributes to neuronal dysfunction and behavioural changes PubMed:30046111
Extracellular deposition of amyloid-β aggregates, the main constituent of senile plaques, is considered to be a pathological hallmark of Alzheimer’s disease that contributes to neuronal dysfunction and behavioural changes PubMed:30046111
Extracellular deposition of amyloid-β aggregates, the main constituent of senile plaques, is considered to be a pathological hallmark of Alzheimer’s disease that contributes to neuronal dysfunction and behavioural changes PubMed:30046111
On the contrary, no relationship between total Aβ plaque burden and number of astrocytes or neurons was found (da Rocha-Souto et al. 2011). PubMed:29196815
On the contrary, no relationship between total Aβ plaque burden and number of astrocytes or neurons was found (da Rocha-Souto et al. 2011). PubMed:29196815
The amyloid plaques associated with AD were first purified and found to consist of multimeric aggregates of Abeta polypeptide containing about 40 amino acid residues in the mid-1980s (Glenner and Wong 1984; Masters et al. 1985) PubMed:22122372
gamma-Secretase further cleaves C99 to release AICD and the amyloidogenic Abeta peptide which aggregates and fibrillates to form amyloid plaques in the brain PubMed:22122372
AD is a chronic neurodegenerative disease characterized by the progressive deposition of the amyloid b (Ab) in the parenchyma of the brain. PubMed:21718217
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