This review discusses recent research highlighting the complex role of mTOR associated with the presence of two hallmarks of AD pathology, senile plaques (composed mostly of fibrillar Aß peptides), and NFT (composed mostly of hyperphosphorylated tau protein).
Here, we found that TRPC1 deletion did not affect learning and memory in physiological conditions, while it aggravated learning and memory deficits induced by amyloid-β (Aβ), the major component of the senile plaques observed in the brains of Alzheimer's disease (AD).
Angiotensin II (AngII) via AT1 receptor is reported to increase brain Aβ level via different mechanisms including increasing amyloid precursor protein (APP) mRNA, β-secretase activity, and presenilin expression.
Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores.
This study reveals a new function of aspirin in stimulating lysosomal biogenesis via PPARα and suggests that low-dose aspirin may be used in lowering storage materials in Alzheimer's disease and lysosomal storage disorders.<b>SIGNIFICANCE STATEMENT</b> Developing drugs for the reduction of amyloid β containing senile plaques, one of the pathological hallmarks of Alzheimer's disease (AD), is an important area of research.
Angiotensin II (AngII) via AT1 receptor is reported to increase brain Aβ level via different mechanisms including increasing amyloid precursor protein (APP) mRNA, β-secretase activity, and presenilin expression.
Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10<sup>-8</sup>) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10<sup>-8</sup>).
Immunohistochemical analyses in human temporal cortical sections with a validated antibody for TLR-3 predominantly identified microglia, particularly strongly in cells associated with amyloid plaques, also brain vascular endothelial cells and subsets of astrocytes, but not neurons or p62-immunoreactive structures.
<i>Rt</i> (10 <i>μ</i>g/ml) significantly inhibited the mean protein level of interleukin-1<i>β</i> (IL-1<i>β</i>) in the organotypic hippocampal slice cultures following treatment with chromogranin A (CGA, 10 nM) and pancreastatin (10 nM), endogenous microglial activators present in senile plaques.
Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10<sup>-8</sup>) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10<sup>-8</sup>).
Angiotensin II (AngII) via AT1 receptor is reported to increase brain Aβ level via different mechanisms including increasing amyloid precursor protein (APP) mRNA, β-secretase activity, and presenilin expression.
The C-terminal sortilin antibody, which labeled senile plaques in the AD human cerebral sections, did not display extracellular immunolabeling in the transgenic mouse or aged monkey brain sections with Aβ deposition.
At the extracellular level, HPSE was observed only in neuritic plaques with a fragmented core, while HPSE2 appeared in those with compact cores as well.
Pharmacological blockade of both COX-1/2 and 5-LOX was able to counteract the progression of AD by targeting pathophysiological mechanisms up- and downstream of Aβ and tau.
At the extracellular level, HPSE was observed only in neuritic plaques with a fragmented core, while HPSE2 appeared in those with compact cores as well.
TGFβ2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble Aβ42 concentration, but not with neuritic plaque scores, total Aβ42, or monomeric α-synuclein immunoreactivity.
Together, our data show that RTN1 and RTN3 have differential effects on the formation of senile plaques in Alzheimer's brains and that RTN3 has a more prominent role in Alzheimer's pathogenesis.
Overall, our results support the hypothesis that the miR-132/212 network, including Sirt1 and likely other target genes, contributes to abnormal Aβ metabolism and senile plaque deposition in AD.
Overall, our results support the hypothesis that the miR-132/212 network, including Sirt1 and likely other target genes, contributes to abnormal Aβ metabolism and senile plaque deposition in AD.