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Advanced Neurology HS-proteoglycans and brain function

exacerbates tau hyperphosphorylation in mouse models. αsyn toxicity. The conserved central region of PrP acts as
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APOE4-mediated surface trafficking of APOE receptor, a linker between the N- and globular C-terminal domains,
LRP-1, through GPC4 promotes tau spreading. 71 facilitating a regulatory metal ion-dependent interaction
between the C- and Ntermini, which attenuates Nterminal
7.5. Collagen XVIII toxicity. 75
Collagen XVIII is well known for its role in stabilizing
networks within basement membranes and the BBB. 8.2. Tau protein
Mutations in collagen XVIII are associated with structural Tau protein has a molecular weight of 55 – 62 kDa and
brain abnormalities in Knobloch syndrome. Endostatin, contains a central domain containing several tubulin-
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a fragment of collagen XVIII, is upregulated in traumatic interactive modules, a Cterminal tail, and an Nterminal
lesions in the brain and spinal cord. Structurally altered domain. Tau stabilizes microtubules in the cytoskeleton,
basement membranes and hydrocephalus have been noted which control cell shape. Tau contains multiple
in collagen XVIII-deficient mice. Aberrant neuronal tubulin-interactive domains and up to 79 Ser and Thr
deposition of endostatin occurs in vascular senile plaques phosphorylation sites. Pathological tau aggregation
and vascular amyloid deposits in AD. occurs in a large group of neurodegenerative diseases
known as tauopathies. The formation of tau aggregates
7.6. Agrin is triggered by two hexapeptide motifs within tau: plant

Agrin, which is associated with αsyn in Lewy bodies in homeodomain finger protein 6 (PHF6) and PHF6*.
PD, accelerates the formation of insoluble protofibrils. These motifs play critical roles in the development and
Agrin abnormalities in the microvasculature and preservation of the CNS. Tau can become dysfunctional
brain parenchyma are linked to Aβ deposition in AD, through misfolding, and its accumulation in the brain
contributing to the pathogenesis of both AD and PD can lead to AD, Down’s syndrome, and dementia. The tau
through pathological lesions. 73 microtubular domain forms a core structure in the helical
PHF6* and PHF6 filaments, promoting tau aggregation.
7.7. Perlecan Post-translational acetylation in PHF6* and PHF6
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Perlecan is immunolocalized within Aβ deposits in blood further promotes tau misfolding. Direct inhibition of
vessels in the AD brain and accumulates in fibrillar Aβ tau aggregation is a promising treatment strategy for the
deposits, where it accelerates and stabilizes amyloid reduction of neurofibrillary tangles in AD. Tau protein
fibril formations. Domain V of perlecan interacts with inhibitory compounds, such as phenothiazines, have
the α2 integrin; Aβ is also a ligand for α2β1 and αvβ1, successfully modulated the pathophysiology of several
mediating Aβ-induced activation of cJun and caspase3 neurodegenerative diseases.
in the neurotoxic pathway in primary cortical and 8.3. Synuclein
hippocampal neurons. Perlecan domain V modulates
α2β1-mediated neurotoxic effects and also interacts with α-synuclein is a small, unstructured, presynaptic protein
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the α5β1 integrin receptor and VEGFR2, increasing VEGF that localizes in the nucleus and mitochondria of axonal
production and promoting angiogenesis, which improves terminal pre-synaptic neurons, where it interacts with
BBB repair following stroke. The HS chains of perlecan tubulin and phospholipids and regulates neurotransmitter
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play critical roles in amyloid fibril assembly, both in vitro in trafficking. In PD and dementia, αsyn aggregates into large
microglia and in vivo in microglia/macrophages following protein deposits known as Lewy bodies, which are linked to
the infusion of Aβ protein into the rodent hippocampus. 74 neurotoxic pathways, including lysosomal, mitochondrial,
and synaptic dysfunction, as well as endoplasmic reticulum
8. Pathological features and treatment of and oxidative stress. 77,78 Tau deposits often occur alongside
insoluble protein deposits in brain tissues α-syn aggregates in PD brains. Tau accelerates the
formation of α-syn fibril, contributing to the pathogenesis
8.1. Prion
of PD. Tau-modified αsyn fibrils exhibit enhanced
Normal prion glycoprotein is a GPI-anchored protein seeding properties, induce mitochondrial dysfunction,
located in the outer membrane of neurons. It has a flexible impair synaptic function, and contribute to neurotoxicity.
tail and a structured core that interacts with a wide range Injection of tau-modified α-syn fibrils into animal models
of partners, playing physiological roles in regulating the induces severe pathological changes in the brain, leading
homeostasis of peripheral nerve myelination. Misfolding of to motor dysfunction and cognitive impairment. Tau
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PrP causes prion disease and mediates βoligomer-induced knock-out models show attenuation of tau-mediated
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neurotoxicity in AD and PD. SDC1 mediates prion-like pathological changes in PD mice. Aggregates of αsyn

Volume 3 Issue 3 (2024) 10 doi: 10.36922/an.3812