Arterial and arteriolar amyloid-beta (A beta) deposition in hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D) and Alzheimer disease (AD) cerebral amyloid angiopathy (CAA) were studied as to morphology, extent, and association with mononuclear phagocyte system (MPS) cells using A beta, a-smooth muscle actin, and monocyte/macrophage marker (HLA-DR, CD68, CD11c, CD45) immunohistochemistry.
The levels of peroxidation handling (CAT, GSHPx, and GSSG-R) mRNAs normalized to beta-actin mRNA level were elevated in hippocampus and inferior parietal lobule, but not in cerebellum of AD patients, which may reflect the protective gene response to the increased peroxidation in the brain regions showing severe AD pathology.
The relationships between ApoE, TTR and actin could suggest a metabolic implication of ApoE genetics and TTR levels in cytoskeletal biochemistry which may be relevant to the pathogenesis of AD.
We found significantly increased DNAse I transcripts in brain of DS and AD both, when normalized versus the house-keeping gene beta actin or total RNA.
To assess the importance of potential confounders TaqMan real-time RT-PCR was used to measure seven mRNAs (beta-actin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), cyclophilin, microtubule-associated protein (MAP) 2, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), amyloid precursor protein (APP) isoform 770) in cortical samples taken from 90 Alzheimer's disease (AD) and 81 control brains.
Further, using real-time PCR analysis, we found that beta-actin and 18S rRNA are differentially expressed in the brain specimens of both AD and control subjects, while GAPDH is similarly expressed in AD and control brain specimens.
In order to furnish a combined model of relevance to human inclusion-body myopathy and Alzheimer's disease, transgenic mice expressing human betaAPP-C99 in skeletal muscle and brain under the control of the cytomegalovirus/beta-actin promoter were produced (Tg13592).
While vascular Abeta deposition was invariably associated with smooth muscle degeneration as indicated by absence of smooth muscle cell actin reactivity, VaD/MD cases exhibited markedly more vascular Abeta(42) deposits and smooth muscle actin loss compared to AD cases with similar degrees of CAA and Abeta(40) deposition.
In comparison with non-AD control subjects, smooth muscle actin was decreased in patients clinically diagnosed with AD and was reduced >10-fold in cases with AD pathology (Braak I to VI) compared with those lacking AD neuropathology.
The requirement of activated ADF/cofilin for the sequestration of pMAP suggests that neuropil thread structures in the AD brain may be initiated by elevated cofilin activation and F-actin bundling that can be caused by oxidative stress, mitochondrial dysfunction, or Abeta peptides, all suspected initiators of synaptic loss and neurodegeneration in AD.
Frequently used housekeepers such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and β-actin had lower overall expression in AD and AD/LBD cases than in controls.
Mutant huntingtin induces a dominant, persistent nuclear rod phenotype similar to that described in Alzheimer's disease for cytoplasmic cofilin-actin rods.
The significant changes in protein levels of actin, immunoglobulin lambda light chain and protein phosphatase 2 were noteworthy given their functional roles in AD pathogenesis.
Cofilin-actin rods provide a mechanism for synapse loss bridging the amyloid and cytokine hypotheses for Alzheimer disease, and may explain how functionally diverse Aβ-binding membrane proteins induce synaptic dysfunction.
These data suggest deregulated Src-dependent signaling pathways involving GluN2B-composed NMDARs and post-synaptic actin cytoskeleton depolymerization in the hippocampus in early stages of AD.
Dysregulation of the actin cytoskeleton, which plays a key role in regulating the integrity of synapses and the transport of synaptic proteins, has been suggested to contribute to the pathology of AD.
In addition, aberrant interaction of the microtubule-associated protein Tau with filamentous actin is connected to synaptic impairment in Alzheimer's disease.
Malfunctions of the actin binding protein Drebrin have been implicated in various human diseases such as Alzheimer's disease, cognitive impairments, cancer, and digestive disorders, though with poorly understood mechanisms.
After validating select hits in focused miniscreens, orthogonal assays and primary human macrophages, we show that (1) the previously uncharacterized gene NHLRC2 is a central player in phagocytosis, regulating RhoA-Rac1 signaling cascades that control actin polymerization and filopodia formation, (2) very-long-chain fatty acids are essential for efficient phagocytosis of certain substrates and (3) the previously uncharacterized Alzheimer's disease-associated gene TM2D3 can preferentially influence uptake of amyloid-β aggregates.