Biology subjects

Alladi, P. A.

Publications and source records attributed to Alladi, P. A..

4 recordsLinked to original sources

bioRxiv2023

Fibrinogen and complement factor H: The two crucial markers of Parkinson's disease with cognitive impairment

Animal model-assisted validation is vital for biomarker studies. It provides better means for understanding disease pathogenesis and opens avenues for addressing therapeutics. Our earlier non-targeted label free proteomics-based biomarker study on CSF of Parkinsons disease (PD) patients with cognitive impairment (PDCI), revealed the presence of elevated levels of fibrinogen and complement factor H (CFAH) in PDCI-CSF. In the present study, we aimed to determine if these proteins harbor a pathogenic potential, when present above physiological levels. Native fibrinogen and recombinant CFAH were intraperitoneally injected in adult C57BL/6J mice and 48h later, motor and cognitive behavioral deficits as well as their neuroanatomical correlates were noted. The reduction in stride length in fibrinogen and CFAH injected mice indicate shuffling gait, often seen in PD patients. Motor deficit was complemented by the loss of dopaminergic (DA) neurons in SNpc, compensatory hypertrophy of the surviving neurons, and reduction in TH expression in striatum, thus reminiscing PD pathology. The low discrimination index in (novel object recognition) NOR test complemented by morphological alterations in Nissl-stained CA-1 and subiculum neurons in the fibrinogen-injected mice imply recognition memory deficits. Thus, our study provides objective evidence that fibrinogen and CFAH harbor the potential to induce motor deficits and cognitive impairments in mice, akin to the PDCI-associated neuro-pathological deficits, and thus are potential biomarkers.

neuroscience↗

bioRxiv2022

Apoptotic factors and mitochondrial complexes assist determination of strain-specific susceptibility of mice to Parkinsonian neurotoxin MPTP

Identification of genetic mutations in Parkinsons disease (PD) promulgates the genetic nature of disease susceptibility. Resilience-associated genes being unknown till date, the normal genetic makeup of an individual may be determinative too. Our earlier studies comparing the substantia nigra (SN) and striatum of C57BL/6J, CD-1 mice and their F1-crossbreds demonstrated neuroprotective role of admixing, against the neurotoxin MPTP. Further, the differences in levels of mitochondrial fission/fusion proteins in the SN of parent strains, imply effect on mitochondrial biogenesis. Our present investigations suggest that the baseline levels of apoptotic factors Bcl-2, Bax and AIF differ across the three strains and, are differentially altered in SN following MPTP-administration. The reduction in complex-I levels exclusively in MPTP-injected C57BL/6J, reiterate mitochondrial involvement in PD pathogenesis. The MPTP-induced increase in complex-IV, in the nigra of both parent strains may be compensatory in nature. Ultrastructural evaluation showed fairly preserved mitochondria in the dopaminergic neurons of CD-1 and F1-crossbreds. However, in CD-1, the endoplasmic reticulum demonstrated distinct luminal enlargement, bordering onto ballooning, suggesting proteinopathy as a possible initial trigger. The increase in -synuclein in the pars reticulata of crossbreds suggests a supportive role for this output nucleus in compensating for the lost function of pars compacta. Alternatively, since -synuclein over-expression occurs in different brain regions in PD, the -synuclein increase here may suggest similar pathogenic outcome. Further understanding is required to resolve this biological contraption. Nevertheless, admixing reduces the risk to MPTP by favouring anti-apoptotic consequences. Similar neuroprotection may be envisaged in the admixed populace of Anglo-Indians.

neuroscience↗

bioRxiv2021

Fibrinogen and Complement Factor H are promising CSF protein biomarker(s) for Parkinson's disease with cognitive impairment- A Proteomics and ELISA based study

Cognitive impairment is a debilitating non-motor symptom of Parkinsons disease (PD). The diagnosis of PD with cognitive impairment (PDCI) is essentially through clinical and neuropsychological examinations. There is an emerging need to identify biomarker(s) to foresee cognitive decline in PD patients, at an early stage. We performed label-free unbiased nontargeted proteomics (Q-TOF LC/MS-MS) in CSF of non-neurological control (NNC); PDCI; PD and normal pressure hydrocephalus (NPH), followed by targeted ELISA for validation. The diagnosis was confirmed by neuropsychological and MRI assessments prior to CSF collection. Of the 282 proteins identified by mass spectrometry, 42 were differentially altered in PD, PDCI and NPH. Further, 28 proteins were altered in PDCI and 25 in NPH. An interesting overlap of certain proteins was noted both in PDCI and NPH. Five significantly upregulated proteins in PDCI were fibrinogen, gelsolin, complement factor-H, apolipoprotein A-IV and apolipoprotein A-I. Whereas carnosine dipeptidase 1, carboxypeptidase E, dickkpof 3 and secretogranin 3 precursor proteins were down-regulated. NPH also had few uniquely altered proteins viz. insulin-like growth factor-binding protein, ceruloplasmin, -1 antitrypsin, VGF nerve growth factor, neural cell adhesion molecule L1 like protein. Interestingly, the ELISA-derived protein concentrations correlated well with the neuropsychological scores of certain cognitive domains. Executive function was affected both in PDCI and NPH. In PD, Wisconsin card sorting test (WCST) percentile correlated positively with ApoA-IV and negatively with the ratio of ApoAI: ApoA-IV. Thus assessment of a battery of proteins like fibrinogen--chain, CFAH and ApoAI: ApoA-IV ratio alongside neuropsychological could be reliable biomarkers to distinguish PDCI and NPH.

neuroscience↗

bioRxiv2020

Ageing and MPTP- sensitivity depend on molecular and ultrastructural signatures of astroglia and microglia in mice nigra

Both astroglia and microglia show region-specific distribution in CNS and often maladapt to age-associated alterations within their niche. Studies on autopsied substantia nigra (SN) of Parkinsons disease (PD) patients and experimental models propose gliosis as a trigger for neuronal loss. Epidemiological studies propose an ethnic bias in PD prevalence, since Caucasians are more susceptible than non-whites. Similarly, different mice strains are variably sensitive to MPTP. We had earlier likened divergent MPTP-sensitivity of C57BL/6J and CD-1 mice with differential susceptibility to PD, based on the numbers of SN neurons. Here, we examined whether the variability was incumbent to inter-strain differences in glial features of male C57BL/6J and CD-1 mice. Stereological counts showed relatively more microglia and fewer astrocytes in the SN of normal C57BL/6J mice, suggesting persistence of an immune-vigilant state. MPTP-induced microgliosis and astrogliosis in both strains, suggests their involvement in pathogenesis. ELISA of pro-inflammatory cytokines in the ventral-midbrain revealed augmentation of TNF- and IL-6 at middle-age in both strains that reduced at old-age, suggesting middle-age as a critical, inflamm-aging associated time-point. TNF- levels were high in C57BL/6J, through aging and post-MPTP; while IL-6 and IL-1{beta} were upregulated at old-age. CD-1 had higher levels of anti-inflammatory cytokine TGF-{beta}. MPTP-challenge caused upregulation of enzymes MAO-A, MAO-B and iNOS in both strains. Post-MPTP enhancement in fractalkine and hemeoxygenase-1; may be neuron-associated compensatory signals. Ultrastructural observations of elongated astroglial/microglial mitochondria vis-a-vis the shrunken ones in neurons, suggest a scale-up of their functions with neurotoxic consequences. Thus, astroglia and microglia modulate aging and PD-susceptibility. HighlightsO_LISubstantia nigra of C57BL/6J and CD-1 show no baseline differences in glial numbers C_LIO_LIBoth mice show age and MPTP-induced gliosis in the substantia nigra pars compacta C_LIO_LICD-1 nigra has lower levels of pro- and higher levels of anti-inflammatory cytokines C_LIO_LITilt of balance between pro- and anti-inflammatory cytokines begins at middle age C_LIO_LIAstrocytes and microglia show elongated mitochondria and intact ER upon MPTP-injection C_LI

neuroscience↗