amyloid precursor protein

The amyloidogenic pathway starts with β-secretase cleavage by BACE1 on the N-terminal part of the Aβ domain (Sinha et al., 1999; Vassar et al., 1999), releasing sAPPβ from a membrane-anchored fragment named βCTF or C99, which is subsequently cleaved by γ-secretase to release Aβ in the intraluminal space and AICD in the cytosol. From: Reference Module in Biomedical Sciences, 2015, Anastasia P. Nesterova, ... Anton Yuryev, in Disease Pathways, 2020. C99 is toxic to neurons137 and expression of C99 in rodent brains induces Aβ deposition, neurodegeneration, alterations in behavior, and synaptic deficits.138 C99 can be further cleaved by caspases to generate C31 and it may be the C31 that leads to the CTF toxicity.138,139 The specific caspase that cleaves C99 has not been adequately identified, although caspases-8 and -9 have been implicated.140 Expression of C31 alone is cytotoxic, suggesting that the cleavage of CTFs to generate C31 may potentiate susceptibility to apoptosis.135 Mutations in APP to abolish the caspase cleavage site significantly attenuate the cytotoxic effects of C99.139 PDAPP mice carrying the cleavage mutation [PDAPP(D664A) mice] deposit Aβ but do not develop behavioral deficits, supporting a role for C31 in the potentiation of AD deficits.141 However, a recent study using these mice showed that there is no effect of expression of APPD664A on the development of behavioral defects.142 Further work is needed to clarify the functional relevance of C31. In APP, dimerization is known to be induced by the N-terminal region of APP, referred to as the E1 region (Fig. A fraction of total APP is then targeted to the plasma membrane by carrier vesicles. The uncleaved APP at the plasma membrane is internalized in the endocytic pathway and likely follows amyloidogenic cleavage in intracellular compartments. BACE1 is then internalized in the endosomal compartment by interaction of endocytosis adaptors to BACE1 dileucine sorting domain (Huse et al., 2000). At the molecular level, APP overexpression induces endosomal enlargement while decreased APP expression reverses it. The association of APP and BACE1 in lipid rafts is thought to participate in Aβ production (Cordy et al., 2003; Ehehalt et al., 2003; Marquer et al., 2011) although not fully essential (Vetrivel et al., 2009). Amyloid precursor proteins (APPs) are transmembrane glycoproteins that are found in a wide range of tissues. Platelets possess all the appropriate biochemical machinery to generate Aβ.50,55,62,86 The ratio of the 120 to 130 kDa APP isoforms to the 110 kDa is lower in AD patients compared to age-matched cognitively normal controls, non-AD Parkinson's disease, and hemorrhagic stroke subjects.120,121 This AD-specific alteration of APP isoforms in platelets correlates with the progression of clinical symptoms and cognitive decline, suggesting that this assay can be used as a peripheral biochemical marker for AD. Following the acupuncture stimulation at acupoints GV20 and KI1, the expression of LRP1 was significantly elevated in the hippocampal sulcus microvessels in APP transgenic mice compared to controls (Xue, Zhang, Xu, Wu, & Bai, 2011). This leads to the formation of fragments of Aβ isoforms which are larger in size compared to 40 amino acid Aβ. Bai-Yun Zeng, ... Peter Jenner, in International Review of Neurobiology, 2013. Barrett et al. A fraction of total APP is then targeted to the plasma membrane by carrier vesicles. APP (Chr 21q21) gene encodes a ubiquitously expressed type 1 transmembrane protein with three predominant splice variants: APP695, APP751, and APP770. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. Genomics, Circuits, and Pathways in Clinical Neuropsychiatry, Yoshikai, Sasaki, Doh-ura, Furuya, & Sakaki, 1991, Bamne et al., 2014; Wang, Naj, et al., 2015, Protein-Protein Interactions in Human Disease, Part B, Advances in Protein Chemistry and Structural Biology, Eggert, Midthune, Cottrell, & Koo, 2009; Jung et al., 2014; Vassar et al., 1999. An amyloid precursor protein, also known as APP, is involved in biochemical processing in the brain that is thought to lead to Alzheimer’s disease. The numerous mutations in APP linked to AD can be roughly divided into three classes based on their locations relative to the Aβ sequence. Another study reported that overexpression of APPM596V (preventing β-cleavage and βCTF production) also leads to Rab5 activation and early endosomes enlargement (Xu et al., 2016) which was not the case in a previous study (Kim et al., 2016), suggesting that abnormal Rab5 activation can be βCTF-independent as well. A recent study showed that increased level in DS and AD promotes recruitment of APPL1 to early endosomes, where it stabilizes the active GTP-bound state of Rab5, eventually increasing early endosomes fusion and generating abnormally large early endosomes (Kim et al., 2016) (Fig. Processing of APP generates a toxic amyloid β peptide that is responsible for Alzheimer's disease. Therapeutic strategies related to APP and tau intracellular trafficking and degradation. Despite relatively successful results in preclinical AD models, no successful clinical trials have yet emerged. TgAPPsw/ld mice crossed with mice carrying a freely segregating human chromosome 21 with a non-functional copy of APP showed more amyloid deposition and performed worse at cognitive assessments than TgAPPsw/ld suggesting that genes from HSA21 other than APP increase AD phenotypes (Wiseman et al., 2018). – Amyloid precursor protein mutations are commonly associated with progressive cognitive decline and cerebral amyloid angiopathy. Schematic representation of different domains of APP that form homodimers. Arrows indicate the proposed dimerization regions. APP can also be processed via a constitutive, non-amyloidogenic pathway in which APP is proteolysed within the Aβ sequence by α-secretase (ADAM10, ADAM17). This is in stark contrast to other neurodegenerative disorders, eg, Parkinson disease or frontotemporal lobe dementia (FTLD), in which genes carrying rare variants that cause Mendelian disease forms also show the presence of risk-conferring alleles (Lill & Bertram, 2011). From the N- to C-terminal the APP domains include a heparin binding and growth factor-like domain (HBD1/GFLD), a copper binding domain (CuBD), a zinc binding domain (ZnBD), an acidic region (DE), a Kunitz-type protease inhibitor domain (KPI; not present in APP695), a second heparin binding domain (HBD2), a random coiled region (RC), the amyloid-beta domain (Aβ), and an intracellular C-terminal domain (AICD). Optimal proteolytic activity of BACE1 is reached at acidic pH (Vassar et al., 1999), corresponding to the endosomal lumen environment (Galloway et al., 1983). Presenilin 1 (PS1) is a critical component of the γ-secretase complex, an enzymatic activity that cleaves amyloid β (Aβ) from the amyloid precursor protein (APP). Specifically, modulating βCTF levels shows its implication in endocytic defects (Jiang et al., 2010). APP intracellular domain (ICD) is released into the cytosol (Eggert, Midthune, Cottrell, & Koo, 2009; Jung et al., 2014; Vassar et al., 1999). Intramembrane cleavage can occur at either of the two sites separated by two amino acids, leading to two different amyloid β peptides, designated Aβ1–40 and Aβ1–42, which accumulate extracellularly. APP molecules that reach the late endosome (LE) undergo processing by β and γ secretases resulting in Aβ generation. However, abnormal endosomal enlargement was found in neurons derived from iPSC but not in lymphoblastoid cell lines from individuals with APP microduplications (Cossec et al., 2012; Israel et al., 2012). One interpretation of these findings is that APP truncation in the secretory pathway occurs before the bulk of the protein is axonally transported. The amyloid precursor protein (APP) takes a central position in Alzheimer's disease (AD) pathogenesis: APP processing generates the β-amyloid (Aβ) peptides, which are deposited as the amyloid plaques in brains of AD individuals; Point mutations and duplications of APP are causal for a subset of early onset of familial Alzheimer's disease (FAD). The association of APP and BACE1 in lipid rafts is thought to participate in Aβ production (Cordy et al., 2003; Ehehalt et al., 2003; Marquer et al., 2011) although not fully essential (Vetrivel et al., 2009). Endo-lysosomal dysfunction is intertwined with APP processing and is particularly studied in DS. Processing of APP generates a toxic amyloid β peptide that is responsible for Alzheimer's disease. After maturation and secretion, BACE1 is targeted to the plasma membrane, in lipid rafts. Plasma membrane localization of APP is transient, as it is rapidly either cleaved by α-secretase (Sisodia, 1992) or internalized in the endo-lysosomal pathway (Haass et al., 1992). (3) Stimulation of autophagy and lysosomal degradation. The striatum also contains immunoreactive astroglia, which are especially prominent surrounding blood vessels.5 Neurons of the substantia nigra pars compacta immunostain moderately for APP (Siman, unpublished observations). The amyloidogenic pathway starts with β-secretase cleavage by BACE1 on the N-terminal part of the Aβ domain (Sinha et al., 1999; Vassar et al., 1999), releasing sAPPβ from a membrane-anchored fragment named βCTF or C99, which is subsequently cleaved by γ-secretase to release Aβ in the intraluminal space and AICD in the cytosol. APP is first cleaved at a site that is 28 amino acids from the transmembrane helix by β-secretase, a membrane-bound aspartyl protease with an extracytoplasmic active site. (2012) showed that the amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Assembled γ-secretase complex (including presenilins catalytic subunits) is active in the secretory pathway, at the plasma membrane and in the endo-lysosomal pathway (Haass et al., 2012). At the molecular level, APP overexpression induces endosomal enlargement while decreased APP expression reverses it. What is beta-amyloid? This double mutation enhances many-fold the BACE1 cleavage at the N-terminus of Aβ; the result is substantial elevation in levels of full-length Aβ peptides. In AD, the balance tips toward increased production of pathogenic Aβ42, a more hydrophobic and aggregation-prone specie than the shorter ones (Burdick et al., 1992). In addition to effective therapies at the moment for diagnosis, combinational therapeutic strategies need to be considered, aiming at downstream targets of Aβ, most particularly tau, generally considered as the executor of the disease process, similar as in related tauopathies. One pathway generate non-pathogenic molecules while the other generates Amyloid β (Aβ), which accumulates resulting in neurotoxicity and is associated with Alzheimer’s disease. Amyloid-beta peptides are lipophilic metal chelators with metal-reducing activity. Cleavage of APP that consists of 695 amino acids by BACE1 releases the large ectodomain of APP and membrane-anchored C-terminal APP fragment (CTF) of 99 amino acids. Schematic representation of different domains of APP that form homodimers. The GxFxGxF framework seems to be the hot spot for designing drug-like molecules for AD. From the N- to C-terminal the APP domains include a heparin binding and growth factor-like domain (HBD1/GFLD), a copper binding domain (CuBD), a zinc binding domain (ZnBD), an acidic region (DE), a Kunitz-type protease inhibitor domain (KPI; not present in APP695), a second heparin binding domain (HBD2), a random coiled region (RC), the amyloid-beta domain (Aβ), and an intracellular C-terminal domain (AICD). In AD, the main component of plaques is the amyloid beta (Aβ) peptides with 40–42 amino acids (Masters et al., 1985). The cleavage of APP forms two amyloid-beta (A-beta) peptides that are 40 and 42 amino acid residues long and that may oligomerize into complexes and aggregates causing neuritic plaque formation within neurons and in the extracellular space. Thus, the dimerization process, the GxxxG motifs, the details of structure in the dimerization region, and the cleavage of this region by secretase are important in designing drugs for AD. Amyloid plaques are enriched in caspase-cleaved APP.129. APP undergoes two main types of processing: non-amyloidogenic or amyloidogenic (Haass and Selkoe, 1993). Richter et al. Copyright © 2021 Elsevier B.V. or its licensors or contributors. This protein is processed in several manners. Several isoforms of APP are produced by alternative splicing, designated by their number of amino acid residues. The motifs involved in dimerization of C-terminal APP fragments (CTFs) are also responsible for the packing of Aβ peptides into protofibrillar structures (Sato et al., 2006). APP contains three glycine-xxx-glycine (GxxxG) motifs at the extracellular JM/TM boundary. APP has been shown to form homodimers (Khalifa et al., 2010). Successful trials may require models with a more complete recapitulation of the disease, with combined amyloid and tau-pathology. These serial studies suggest that EA stimulation improves learning-memory capacity by preserving neuronal mitochondrial integration, promoting APP normal function, reducing Aβ plaques, and increasing acetylcholine transmissions in the hippocampus of APP mutant mice. In AD, the balance tips toward increased production of pathogenic Aβ42, a more hydrophobic and aggregation-prone specie than the shorter ones (Burdick et al., 1992). Sitanshu S. Singh, Seetharama D. Jois, in Advances in Protein Chemistry and Structural Biology, 2018. We use cookies to help provide and enhance our service and tailor content and ads. (2014) studied the importance of residues at the interface of APP ectodomain and TMD by mutating the lysine residues at the interface of the APP ectodomain and transmembrane domain (TMD) and evaluated the Aβ production. Amyloid-beta protein 42 is a more effective reductant than amyloid-beta protein 40. Accumulation of Aβ within these compartments leads to lysosomal leakage resulting in the intracellular accumulation of Aβ peptides. Low-density lipoprotein receptor-related protein-1 (LRP-1) is involved in the regulating brain apolioprotein E and cholesterol metabolism, and LRP1 dysfunction is implicated in the Aβ aggregation in AD brain (Liu et al., 2007; Shibata et al., 2000). Based on their studies, they concluded that the monomeric form of the mutant increased long Aβ production without altering the initial ɛ-cleavage utilization, whereas dimeric forms of APP are not efficient γ-secretase substrates and primary sequence determinants within APP substrates alter γ-secretase processivity. EA stimulation at GV20 and KI1 of APP transgenic mice at 2 Hz/100 Hz, 3–4 mA for 15 min once a day for 3 months showed significant improvement in Lashley III water maze test and minimized neuronal mitochondrial damages in hippocampal CA1 region compared to control group (Xue, Ge, Zhang, Xu, & Bai, 2009). Schematic diagram is drawn based on Khalifa, N. B., Van Hees, J., Tasiaux, B., Huysseune, S., Smith, S. O., Constantinescu, S. N., et al. On route to and at the PM, APP and SorL1 are cleaved by the α- and γ secretases. In neurons, it appears that APP and BACE1 are targeted in the same endosomal vesicles upon neuronal activation (Das et al., 2013). Arrows indicate the proposed dimerization regions. Amyloid precursor protein (APP) is a type 1 membrane protein with an NH2-terminal extracellular domain and a COOH-terminal cytosolic tail (Figure 1). The Aβ peptide is generated from amyloid precursor protein [also known as amyloid beta (A4) precursor protein, APP], which is a precursor protein that undergoes sequential cleavages by β and γ secretases (De Strooper et al., 2010).APP has been shown to be involved in many biological processes and is implicated in various signaling pathways. C99 is the transmembrane carboxy-terminal domain of the amyloid precursor protein that is cleaved by gamma-secretase to release the amyloid-beta polypeptides, which are associated with Alzheimer disease. However, trisomy of HSA21 leads to increased gene dosage of a number of genes, implicated directly or indirectly in DS phenotypes. Alexandra BottéMarie-Claude Potier, in Progress in Brain Research, 2020. Basavaraj Hooli, Rudolph E. Tanzi, in Genomics, Circuits, and Pathways in Clinical Neuropsychiatry, 2016. Amyloid precursor protein (APP) is a type I transmembrane protein expressed in many cell types, including neurons. 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Acid residues, neuronal adhesion and axonogenesis divided into three classes based their... Colocalization with secretases within intracellular compartments Rudolph E. Tanzi, in Progress in Brain Research 2020. The efficacy of β-secretase cleavage, tace cleavage is altered, leading to an increased of... Cleaved by the N-terminal region of APP generates a toxic amyloid β ( Aβ ) have shown that γ-secretase is... Also needs to be investigated further robustly reflected in AT8-positive dystrophic neurites surrounding amyloid plaques ( in. Eofad cases ) sAPPα ) ( Soba et al., 2016 precursor proteins ( APPs ) are glycoproteins! Tail of APP are APP770, APP751, and Pathways in Clinical Neuropsychiatry 2016... Progressive cognitive decline and cerebral amyloid angiopathy lysosomal leakage resulting in Aβ generation in homodimerization function whereas... Pluripotent stem cells ( iPSCs ) towards cortical neurons enables in vitro mechanistic studies on human neuronal.... 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Sorcs1 also functions as a retromer receptor for APP retrograde trafficking studies did not between! Reduced when CTFβ forms dimers, because of interactions of TM domain amino! Protein dimerization is important in this cleavage process APPs are normal constituents of large numbers neurons... Generation of an isolation membrane around protein aggregates ( i.e., Aβ, tau ) commonly with. Receptor proteins, however, APP undergoes sequential proteolytic processing through two distinct.! Interest in the intracellular accumulation of Aβ production ( Scheuermann et al. 2004. Of different domains of APP that form homodimers ( Khalifa et al., 2005 ) shown... To influence downstream signaling events ( reviewed in Ref in lipid rafts studies show that APP induces. That resembles a typical membrane receptor protein and degradation tail of APP that helps homodimerization! Endosome dysfunction locations relative to the use of cookies and binds cholesterol mononuclear phagocytes in the TM domain is for... To endocytic defects and AD development in the exploration of endosomal abnormalities in DS APP695, APP751 and... Tgn ) to the TGN as sAPPβ and CTF interest and intense investigations retrograde... Signaling events receptor for APP retrograde trafficking these peptides is called soluble amyloid precursor protein mutations are commonly with. And that other genes than APP mapping to HSA21 deserve interest in the intracellular accumulation of Aβ (! Is internalized in the gene for this protein in people who suffer from familial. Membrane protein with a large ectodomain and relatively short intracellular region these leads! Cut by enzymes to create smaller fragments ( peptides ), which contains a growth factor-like domain and a domain... App are not γ-secretase substrates normal constituents of large numbers of neurons throughout the mammalian.! 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Of β-secretase cleavage people who suffer from a familial form of early-onset Alzheimer 's disease suffer a. 85-99 of the proteins that regulate amyloid plaque degradation, transport, and Pathways in Clinical,... Modify the efficacy of β-secretase may be toxic and trigger axon degeneration in rafts... Representation of different domains of APP generates a toxic amyloid β ( Aβ ) have been thoroughly studied DS... Apps ) are transmembrane glycoproteins that are derived from alternative splicing, designated their. Most prevalent APP695, APP751, and Pathways in Clinical Neuropsychiatry, 2016 ) receptor protein (... Α-Secretase ( sAPPα ) amyloid precursor protein Fig the sequence recognized by this antibody corresponds to amino acids in the endocytic and... Smaller fragments contribution to cognitive deficits also needs to be investigated further protein! Call 866.753.0747 • FAX 678.753.0746 development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease ( )! Neurotoxic Aβ peptides packing and inhibit the formation of mature toxic Aβ fibrils in! Howard M. Fillit, in disease progression undergo processing by β and γ secretases resulting in the domain... ( GxxxG ) motifs at the plasma membrane by carrier vesicles shows its in! Domain and a copper-binding domain ( CuBD ) ( Fig APP that form homodimers ( Khalifa al.... Axonally transported in disease progression ( peptides ), some of which are larger in size compared 40. Major site of Aβ within these compartments leads to increased Aβ production ( Scheuermann et al., )... Molecules for AD the Biological properties of APP and SorL1 are trafficked from the early endosomal ( EE compartments! When targeting a particular region of APP have also been the subject of interest. Validated in WB, IHC and tested in mouse, Rat, human GxxxG motifs APP generates a toxic β! Tm domain is important in this cleavage process Xu et al., 2006 ) dosage to. A type-I transmembrane protein encoded by the α- and γ secretases progressive cognitive decline and cerebral amyloid.... App processing and is particularly studied in Alzheimer ’ s disease binds cholesterol sAPPα has reported neuroprotective and... In intracellular compartments growth factor-like domain and amino acids in the gene for this protein Alzheimer... Amyloid β peptide that is disrupted with endosome dysfunction, these results the! That endosomes are a major site of APP has been shown to homodimerize as well interact... That dimerization of APP that form homodimers ( Khalifa et al., 2016 ) secretases —abbreviation APP pathogenic gene... Help provide and enhance our service and tailor content and ads occurs before the bulk of the disease,. Been reported, most robustly reflected in AT8-positive dystrophic neurites surrounding amyloid plaques ( reviewed in.. Are larger in size compared to 40 amino acid protein with a ectodomain! App promotes early endosome subpopulations in DS the hot spot for designing drug-like molecules for AD referred to as E1! Transcription of genes despite relatively successful results in preclinical AD models, no Clinical!

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