Role of Extracellular Matrix Changes in Alzheimer's
Alzheimer's disease (AD) is a serious condition where the brain deteriorates due to the buildup of beta-amyloid plaques and tau tangles. It is a leading cause of dementia, and its symptoms progress over time. Age is the primary risk factor for AD, though there are genetic factors that can lead to early-onset AD.
Several classification schemes have been developed to stage the disease, including neuropathological staging and biomarker-based staging. Detecting beta-amyloid, tau, and neurodegeneration markers in cerebrospinal fluid can help diagnose different types of dementia. Magnetic resonance imaging can show the spatiotemporal progression of brain atrophy, with the earliest signs appearing in the amygdala and hippocampus. Molecular and cellular mechanisms that precede neuronal loss have been linked to the development of AD, including inflammation, microglia activation, and synapse dysfunction.
The extracellular matrix (ECM), which is made up of glycoproteins, proteoglycans, link proteins, and hyaluronan, undergoes changes in AD. The lecticans and link proteins are important components of the ECM, and aging-related changes in ECM structure and composition are thought to play a role in neurodegenerative disorders. Perineuronal nets, which are aggrecan-rich structures that surround certain types of neurons, are thought to be protective against tau pathology. The clinically licensed anti-AD drug Memantine has been shown to increase glycosaminoglycans in the ECM, making it a potential therapeutic target.
However, our understanding of the modifications in the neural ECM in AD brains is still incomplete, and previous reports on ECM changes in AD are sometimes contradictory. The WFA lectin binding, which has been used in many studies, may not be a reliable indicator of PNN structure integrity, as it may be influenced by changes in sulfation patterns in carbohydrate structures expressed on ECM proteoglycans. Disturbed ECM-neuron interaction may also be a consequence of changes in proteoglycan solubility or synaptic membrane association.
New study reveals subcellular extracellular matrix rearrangement in Alzheimer's disease brain
A new study aimed to investigate the rearrangement of subcellular extracellular matrix (ECM) components in the human brain during Alzheimer's disease (AD). The researchers used antibodies to detect key components of the hyaluronan-binding neural ECM in subcellular fractions from post-mortem brain areas, i.e., hippocampus, temporal and frontal cortex, to provide a more comprehensive and differentiated picture of subcellular ECM rearrangement during AD. They combined protein biochemical data with RNAseq data from The Aging, Dementia and TBI Study and provided measurements of neural proteoglycans brevican and neurocan and their major proteolytic fragments in human AD and control cerebrospinal fluid samples.
Surprising links between Alzheimer's disease and changes in brain extracellular matrix
Their results showed a significant reduction in full-length brevican in the soluble fraction from the temporal cortex and a significant upregulation of the major 130 kDa neurocan isoform in the S2 fraction from ADhigh as compared to control samples from temporal cortex. The link protein HAPLN1 was significantly upregulated in the ADhigh compared to the control group in the S2 fraction from the frontal cortex.
The researchers also analyzed gene expression of extracellular matrix (ECM) components in Alzheimer's disease (AD) brains. Therefore, they used RNA sequencing data from a database of 107 cases. There findings: There are significant differences in the expression levels of HAPLN1 in the hippocampus between non-demented controls and dementia samples. There were also significant negative correlations between hippocampal expression levels of neurocan and HAPLN1 and Braak stages, but not with protein levels. Furthermore, the brevican interaction partner tenascin-R (TNR) in the hippocampus, temporal cortex, was down-regulated.
Correlations between brain proteins and Alzheimer's disease progression and cognitive decline, but CSF proteoglycans may not be suitable biomarkers
They also detected frontal white matter of dementia samples, with a negative correlation of TNR expression with Braak stages. In addition, RNA levels of neurocan, brevican, and tenascin-R in the brain significantly positively correlated with brain phospho-tau protein levels, but negatively with Aβ1-42 levels and the Aβ ratio. In contrast, aggrecan RNA levels significantly negatively correlated with phospho-tau and the tau ratio, but positively with Aβ1-42 levels and the Aβ ratio.
The authors also investigated the levels of brevican and neurocan in the cerebrospinal fluid (CSF) of AD patients. Interestingly, there were no significant group differences in total concentrations of the two proteoglycans. In the same way, there were no significant differences in cleaved products of brevican and neurocan between groups. This suggests that these measures may not be suitable as biomarkers for AD. However, the researchers found significant positive correlations between CSF proteoglycan concentrations and age, total tau, phosphorylated tau, and Aβ1-40, but not with Aβ1-42 or albumin quotient QAlbumin. Furthermore, they found a significant negative correlation of CSF brevican concentrations with Mini Mental State Examination (MMSE) test results. This suggests a relationship between higher CSF brevican concentrations and cognitive decline.