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.
The Alzheimer's disease (AD) susceptibility gene, CD2-associated protein (CD2AP), encodes an actin binding adaptor protein, but its function in the nervous system is largely unknown.
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.
The actin-binding protein cofilin known for its actin filament severing, depolymerizing, nucleating, and bundling activities has emerged as a significant player in AD pathogenesis.
Finally, we show that important downstream pathways, including autophagy and the unfolded protein response, are coregulated with neurotoxicity and actin cytoskeletal stabilization in brains of flies expressing wild-type human and various FTDP-17 tau mutants, supporting a conserved mechanism of neurotoxicity of wild-type tau and FTDP-17 mutant tau in disease pathogenesis.<b>SIGNIFICANCE STATEMENT</b> The microtubule protein tau aggregates and forms insoluble inclusion bodies known as neurofibrillary tangles in the brain tissue of patients with a variety of neurodegenerative disorders, including Alzheimer's disease.
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.
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.
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.
The intrinsically disordered protein, Tau, is abundant in neurons and contributes to the regulation of the microtubule (MT) and actin network, while its intracellular abnormal aggregation is closely associated with Alzheimer's disease.
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.
In spin-down assay, G-actin fractions of controls displayed two closely spaced bands of actin in SDS-PAGE; while in AD and DS, only the upper band of the doublet was present.
Mutant huntingtin induces a dominant, persistent nuclear rod phenotype similar to that described in Alzheimer's disease for cytoplasmic cofilin-actin rods.
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.
Overall, the results demonstrate marked synaptic disturbances in two actin regulatory proteins in adult DS and AD brains, with greater effects in individuals with AD alone.
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.
In addition, aberrant interaction of the microtubule-associated protein Tau with filamentous actin is connected to synaptic impairment in Alzheimer's disease.
Actin bundling protein 34 (ABP34) is the one of 11 actin-crosslinking proteins identified in Dictyostelium discoideum, a novel model organism for the study of actin-associated neurodegenerative disorders such as Alzheimer's disease and Huntington's disease.
These results provide a novel molecular link between Aβ and actin disruption through dysregulated phosphoinositide metabolism, and the SHIP2-PI(3,4)P<sub>2</sub>-ARAP3-RhoA signaling pathway can be considered as new therapeutic targets for synaptic dysfunctions in Alzheimer's disease.
F-actin decrease correlated inversely with increasing AD pathology (Braak score, Aβ load, and tangle density) and directly with performance in episodic and working memory tasks, suggesting its role in human disease pathogenesis and progression.<b>SIGNIFICANCE STATEMENT</b> Synaptic dysfunction underlies cognitive deficits in Alzheimer's disease (AD).