Alzheimer’s disease (AD) is a neurodegenerative disorder that progressively involves brain regions with an often-predictable pattern. Damage to the brain appears to spread and worsen with time, but the molecular mechanisms underlying the region-specific distribution of AD pathology at different stages of the disease are still under-investigated. In this study, a whole-transcriptome analysis was carried out on brain samples from the hippocampus (HI), temporal and parietal cortices (TC and PC, respectively), cingulate cortex (CG), and substantia nigra (SN) of six subjects with a definite AD diagnosis and three healthy age-matched controls in duplicate. The transcriptomic results showed a greater number of differentially expressed genes (DEGs) in the TC (1571) and CG (1210) and a smaller number of DEGs in the HI (206), PC (109), and SN (60). Furthermore, the GSEA showed a difference between the group of brain areas affected early (HI and TC) and the group of areas that were subsequently involved (PC, CG, and SN). Notably, in the HI and TC, there was a significant downregulation of shared DEGs primarily involved in synaptic transmission, while in the PC, CG, and SN, there was a significant downregulation of genes primarily involved in protein folding and trafficking. The course of AD could follow a definite time- and severity-related pattern that arises from protein misfolding, as observed in the PC, CG, and SN, and leads to synaptic impairment, as observed in the HI and TC. Therefore, a map of the molecular and biological processes involved in AD pathogenesis may be traced. This could aid in the discovery of novel biological targets in order to develop effective and well-timed therapeutic approaches.

Astrogliosis is a condition shared by acute and chronic neurological diseases and includes morphological, proteomic, and functional rearrangements of astroglia. In Alzheimer's disease (AD), reactive astrocytes frame amyloid deposits and exhibit structural changes associated with the overexpression of specific proteins, mostly belonging to intermediate filaments. At a functional level, amyloid beta triggers dysfunctional calcium signaling in astrocytes, which contributes to the maintenance of chronic neuroinflammation. Therefore, the identification of intracellular players that participate in astrocyte calcium signaling can help unveil the mechanisms underlying astrocyte reactivity and loss of function in AD. We have recently identified the calcium‐binding protein centrin‐2 (CETN2) as a novel astrocyte marker in the human brain and, in order to determine whether astrocytic CETN2 expression and distribution could be affected by neurodegenerative conditions, we examined its pattern in control and sporadic AD patients. By immunoblot, immunohistochemistry, and targeted‐mass spectrometry, we report a positive correlation between entorhinal CETN2 immunoreactivity and neurocognitive impairment, along with the abundance of amyloid depositions and neurofibrillary tangles, thus highlighting a linear relationship between CETN2 expression and AD progression. CETN2‐positive astrocytes were dispersed in the entorhinal cortex with a clustered pattern and colocalized with reactive glia markers STAT3, NFATc3, and YKL‐40, indicating a human‐specific role in AD‐induced astrogliosis. Collectively, our data provide the first evidence that CETN2 is part of the astrocytic calcium toolkit undergoing rearrangements in AD and adds CETN2 to the list of proteins that could play a role in disease evolution.

Background: Few studies investigate the correlation between the quantitative EEG (QEEG) and the neuropathological picture. The purpose of this study is to explore how QEEG can recognize the type and extent of neuropathological changes.Method: The EEG traces and brains belonging to 14 donors of the Abbiategrasso Brain Bank were analyzed. The subjects suffered from neurocognitive disorders due to AD, LBD or AD/vascular lesions (mixed dementia‐MD), with different stages of clinical and neuropathological severity. Clinical and neuropathological characterization was performed according to our protocol; biochemical measurements to determine the amount of proteinopathies are in runtime on frozen samples. QEEG analysis considered the relative power distribution (RPD) of the frequency bands (β, α, θ, δ) and the peak frequency (PF), i.e. the most represented frequency considering all the leads. The PF was measured every 2 seconds for 200‐400 samples, and then averaged. The Kruskall‐Wallis test was used for the comparison between groups.Result: The clinical diagnosis included: 2 MCI, 4 AD, 6 MD, and 2 LBD. The neuropathological definite diagnosis demonstrated frequent co‐pathologies, and some discrepancies compared to the clinical diagnosis. The neuropathological characterization identified 2 cases with low AD pathology (corresponding to the 2 MCI), 8 cases with intermediate or high AD pathology (4 MD with concomitant cerebrovascular disease), and 4 cases with prevalent LBD pathology. Considering both clinical and neuropathological diagnoses, the comparison between groups revealed no significant differences in QEEG parameters. Nonetheless, a trend emerges towards a lower β‐RPD and a higher θ‐RPD in cases with prevalent LBD pathology. Grouping based on the severity of AD pathology (2 low, 4 intermediate, 4 high) demonstrated significant differences depending upon the neuropathological scoring with a progressive decrease of α‐RPD (p = 0.029) and PF (p = 0.019), and an increase of δ‐RPD (p = 0.020).Conclusion: RPD and PF show low discriminatory capacity on etiology. Nonetheless, the presence of LBD seems to boost the EEG slowing. The PF slowing down parallels the increase of AD pathology, representing an indicator for the degenerative load. PF is a simple QEEG parameter, easily obtainable through standard digital EEG; it can be useful for monitoring neurodegenerative burden and disease evolution.