Neurodegeneration: Novus Biologicals

Neurodegeneration

Neurodegenerative diseases refer to a group of age-associated conditions with progressive loss of neuronal structure and function, often accompanied by aberrant protein accumulation, resulting in cognitive disability, motor deficits and dementia. The four most common neurodegenerative diseases - Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS) - each have different clinical presentations and affect different neuronal populations and brain areas. However, commonalities have been identified between the diseases, suggesting that abnormal protein aggregation and failure of autophagy, mitochondrial dysfunction and oxidative stress, as well as inflammatory environment and reactive microglia contribute to the development of all these diseases.

Most common neurodegenerative diseases and their pathologies

Neurodegenerative disease	Brain regions affected	Pathology	Major cell types affected
Alzheimer’s Disease	Hippocampus Cerebral cortex	Senile plaques Neurofibrillary tangles Neuronal inclusions	Cholinergic neurons Astrocytes Microglia
Parkinson’s Disease	Substantia nigra Hypothalamus	Lewy bodies	Dopaminergic neurons
Huntington’s Disease	Striatum Cerebral cortex Thalamus	Neuronal inclusions	GABAergic neurons
Amyotrophic lateral sclerosis	Brainstem motor neurons Spinal cord motor neurons Motor cortex	Neuronal inclusions Motor neuron loss	Motor neurons

Explore Neurodegeneration Pathways

Alzheimer's

Alzheimer’s Disease (AD) is marked by a progressive cognitive impairment including memory loss and behavioral changes. Numerous environmental and generic risk factors have been associated with developing this generally sporadic disease. AD is characterized by amyloid-beta accumulation in extracellular neural tissues, as well as intracellular neurofibrillary tangles consisting of phosphorylated tau protein. The result is a deterioration of cholinergic neurons and loss of synaptic function in the hippocampus and cerebral cortex.

Major protein targets involved in AD research

Gene	Protein target	Role in disease
APP	Amyloid precursor protein	Integral membrane protein that is sequentially processed by beta-secretase and gamma-secretase to produce amyloid-beta that can form oligomers and lead to amyloid plaques formation.
PSEN1/PSEN2	Presenilin-1 Presenilin-2	Facilitate gamma-secretase cleavage of APP. Mutations in presenilins increase production of the aggregation prone amyloid-beta variant (Aβ42).
APOE/APOE4	Apolipoprotein E	Major cholesterol carrier, supports lipid transport. ApoE isoforms differentially regulate amyloid-beta aggregation and clearance in the brain. APOE ε4 allele is associated with increased risk of developing AD.
MAPT	Tau	A neuronal microtubule associated protein found in axons. Promotes tubulin polymerization and stabilizes microtubules. Hyperphosphorylated tau is a major component of neurofibrillary tangles.


beta Amyloid Antibody (MOAB-2) [NBP2-13075] - IHC analysis of a formalin fixed paraffin embedded tissue section of human brain (Alzheimer's disease, hippocampus) using 1:200 dilution of anti-beta Amyloid antibody (clone MOAB-2). The staining was developed with HRP labeled anti-mouse secondary antibody and DAB reagent, and nuclei of cells were counter-stained with hematoxylin. This beta Amyloid antibody specifically stained the cells with Abeta 42/ Abeta aggregates.	Presenilin-1 was detected in immersion fixed paraffin-embedded sections of human brain (medulla) using Mouse Anti-Human Presenilin-1 N-Terminal Fragment Monoclonal Antibody (Catalog # MAB149) at 1.7 µg/mL for 1 hour at room temperature followed by incubation with the Anti-Mouse IgG VisUCyte^™ HRP Polymer Antibody (Catalog # VC001). Tissue was stained using DAB (brown) and counterstained with hematoxylin (blue). Specific staining was localized to neuronal cell bodies.	Tau was detected in immersion fixed paraffin-embedded sections of human Alzheimer's brain using Mouse Anti-Tau Monoclonal Antibody (Catalog # MAB3494) at 15 µg/mL overnight at 4 °C. Before incubation with the primary antibody, tissue was subjected to heat-induced epitope retrieval using Antigen Retrieval Reagent-Basic (Catalog # CTS013). Tissue was stained using the Anti-Mouse HRP-DAB Cell & Tissue Staining Kit (brown; Catalog # CTS002) and counterstained with hematoxylin (blue). Specific staining was localized to neuronal cell bodies and processes.

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Parkinson's

Parkinson’s Disease (PD) is a common neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons, mainly in the substantia nigra. It is defined by the presence of alpha-synuclein aggregates (Lewy bodies) and accumulation of defective mitochondria, leading to neuronal death. PD patients display a variety of motor symptoms such as resting tremors, rigidity and postural instability, along with non-motor symptoms including depression, sleep disorder and olfactory dysfunction. Sporadic forms of the disease constitute more than 90% of cases and the onset occurs over the age of 60. Currently, there is no cure for PD, but its motor symptoms can be alleviated temporarily with dopamine inducing approaches. New therapies concentrate on neuroprotective and disease-modifying strategies.

Major protein targets involved in PD research

Gene	Protein target	Role in disease
LRRK2	Leucine rich repeat kinase 2	Most commonly known genetic contributor to PD. Mutations are linked to aberrant inflammatory responses, increased oxidative stress, synaptic dysfunction, abnormal autophagy functions and more.
PINK	PTEN-induced putative kinase 1	A mitochondrial serine/threonine protein kinase with a protective function against stress-induced mitochondrial dysfunction. Targets defective mitochondria for degradation. Mutations in PINK1 lead to accumulation of misfolded proteins in mitochondria.
TH	Tyrosine Hydroxylase	Enzyme that catalyzes the hydroxylation of L-tyrosine to L-DOPA, a critical dopamine precursor.
PARK2	Parkin	Plays a role in the ubiquitin-mediated proteolytic pathway. Loss of parkin E4 ubiquitin ligase function contributes to accumulation of toxic and/or misfolded proteins.
PARK7	Protein deglycase DJ-1	Various roles in transcriptional regulation, oxidative stress response, and mitochondrial function. Senses cellular redox metabolism and scavenges free radicals. Mutations associated with early-onset familial forms of PD.
SNCA	Alpha-synuclein	Involved in the regulation of synaptic transmission and neurotransmitter release. Aggregates of alpha-synuclein correlate with degeneration of dopaminergic neurons. Main component of Lewy bodies.


PINK1 Antibody [NBP1-49678] - Stain in paraffin embedded mouse brain.	Tyrosine Hydroxylase Antibody (5C7.2E8) [NBP2-42211] - Analysis of a FFPE tissue section of human brain /substantia nigra using Tyrosine Hydroxylase antibody (clone 5C7.2E8) at 15 ug/ml concentration. This representative photomicrograph shows strong immunostaining of tyrosine hydroxylase /TH in TH-positive neurons.

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Huntington's

Huntington’s Disease (HD) is marked by a progressive degeneration of neurons of the striatum and cortex. The disease is familial and follows an autosomal dominant inheritance pattern. It is characterized by a polyglutamine repeat expansion in the huntingtin protein that results in formation of neuronal inclusions and subsequent neuronal loss. This leads to movement, psychiatric and cognitive impairments. Patients are usually diagnosed at 40 years of age and have life expectancy of around 15 years. Currently, no cure exists for the disease.

Major protein targets involved in HD research

Gene	Protein target	Role in disease
HTT	Huntingtin	Mutant huntingtin protein forms aggregates and has deleterious effects on neuronal gene transcription, axonal transport and mitochondrial function.
HAP1	Huntington Associated Protein 1	A cytoplasmic protein, interacts with Huntingtin, among other targets in regulating microtubule-dependent transport, vesicular trafficking, nerve growth and transcriptional regulation.
SOD1	Superoxide dismutase	An antioxidant enzyme involved in the defense against reactive oxygen species.
BDNF	Brain derived neurotrophic factor	Pro-survival factor in neurons, required for axonal transport and neuronal survival. Mutant HTT decreases the levels of BDNF leading to reduced neuronal survival.


HAP1 Antibody (1B6) [NB110-74569] - Staining of rat hypothalamus.	BDNF was detected in immersion fixed paraffin-embedded sections of human spinal cord using Chicken Anti-Human BDNF Antigen Affinity-purified Polyclonal Antibody (Catalog # AF248) at 15 µg/mL overnight at 4 °C. Tissue was stained using HRP-DAB detection (brown) and counterstained with hematoxylin (blue).

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ALS

Amyotrophic Lateral Sclerosis (ALS) is a disease of degeneration of motor neurons in the brain and the spinal cord. It is the third most common neurodegenerative disease. Its symptoms include loss of control of muscle movement as well as muscle weakness, atrophy, twitching and cramps. The onset of the disease occurs approximately at 60 years old and patients survive on average three years from diagnosis. Most cases of ALS are sporadic and involve a number of genes, only some identified so far. However, 60% of familial ALS can be attributed to mutations in four genes: SOD1, TDP-43/TARDBP, FUS and C9orf72. Aberrant autophagy and RNA metabolism are two processes heavily implicated in the disease progression. Protein aggregates are also a common feature of ALS.

Major protein targets involved in ALS research

Gene	Protein target	Role in disease
SOD1	Superoxide dismutase	An antioxidant enzyme involved in the defense against reactive oxygen species. Mutations in SOD1 are linked to familial ALS.
TARDBP	TDP-43/ TARDBP	Nuclear RNA/DNA binding phosphoprotein that regulates transcription and splicing in the cell nucleus. Mutations in TDP-43 cause its aggregation within inclusion bodies in the cytoplasm of motor neurons.
FUS	FUS	Mutant variants are involved in abnormal mRNA processing and form aggregates in motor neurons


TDP-43/TARDBP Antibody [NB110-55376] - Total protein from HeLa, MCF7 and mouse brain was separated on a 12% gel by SDS-PAGE, transferred to PVDF membrane and blocked in 5% non-fat milk in TBST. The membrane was probed with 1.0 ug/ml anti-TARDBP in 1% block buffer and detected with an anti-rabbit HRP secondary antibody using chemiluminescence.	C9orf72 Antibody [NBP2-47146] - IHC analysis of a formalin fixed paraffin embedded tissue section of mouse brain using C9orf72 antibody (NBP2-47146) at 1:300 dilution with HRP-DAB detection and hematoxylin counterstaining. The antibody generated strong/specific cytoplasmic signal in the neurons and other cell types in the tested section.

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Content developed by Michalina Hanzel, PhD Postdoctoral Associate at The Rockefeller University. Dr. Hanzel is currently studying synaptic function in the cerebellum to understand neurodevelopmental disorders and has a background in developmental neurobiology, molecular and cell biology.

Select References

Bates, G.P., Dorsey, R., Gusella, J.F. et al. (2015). Huntington disease. Nat Rev Dis Primers. 11-2. https://doi.org/10.1038/nrdp.2015.5

Brown, R.H., Al-Chalabi, A. (2017). Amyotrophic Lateral Sclerosis. N Engl J Med. Jul 13;377(2):162-172. https://doi.org/10.1056/NEJMra1603471

Davis, M., Stroud, C. eds (2013). Neurodegeneration: Exploring Commonalities Across Diseases: Workshop Summary USA: National Academy of Sciences. p4-15.

Dugger, B.N., & Dickson, D.W. (2017). Pathology of neurodegenerative diseases. Cold Spring Harb. Perspect. Biol. 9. https://doi.org/10.1101/cshperspect.a028035

Edwards, F.A. (2019). A Unifying Hypothesis for Alzheimer’s Disease: From Plaques to Neurodegeneration. Trends Neurosci. https://doi.org/10.1016/j.tins.2019.03.003

Irwin, D.J., Lee, V.M., Trojanowski, J.Q. (2013). Parkinson’s disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies. Nat Rev Neurosci. 14(9):626–636. https://doi.org/10.1038/nrn3549

Kumar, A., Singh, A., & Ekavali. (2015). A review on Alzheimer’s disease pathophysiology and its management: An update. Pharmacol. Reports. 67, 195–203. https://doi.org/10.1016/j.pharep.2014.09.004

Penzes, P., Remmers, C., Cahill, M.E., Jones, K.A., VanLeeuwen, J.-E., & Woolfrey, K.M. (2014). Structural Alterations of Synapses in Psychiatric and Neurodegenerative Disorders. In The Synapse, (Elsevier), pp. 281–300. https://doi.org/10.1016/B978-0-12-418675-0.00009-2

Tan, S.H., Karri, V., Tay, N.W.R., Chang, K.H., Ah, H.Y., Ng, P.Q., Ho, H.S., Keh, H.W., & Candasamy, M. (2019). Emerging pathways to neurodegeneration: Dissecting the critical molecular mechanisms in Alzheimer’s disease, Parkinson’s disease. Biomed. Pharmacother. 111, 765–777. https://doi.org/10.1016/j.biopha.2018.12.101