The Interplay Between Beta-Amyloid 1–42 (Aβ1–42)-Induced Hippocampal Inflammatory Response, p-tau, Vascular Pathology, and Their Synergistic Contributions to Neuronal Death and Behavioral Deficits

Abstract

Alzheimer's disease (AD), the most common chronic neurodegenerative disorder, has complex neuropathology. The principal neuropathological hallmarks of the disease are the deposition of extracellular β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau (p-tau) protein. These changes occur with neuroinflammation, a compromised blood-brain barrier (BBB) integrity, and neuronal synaptic dysfunction, all of which ultimately lead to neuronal cell loss and cognitive deficits in AD. Aβ 1-42 was stereotaxically administered bilaterally into the CA1 region of the hippocampi of 18-month-old male C57BL/6 mice. This study aimed to characterize, utilizing immunohistochemistry and behavioral testing, the spatial and temporal effects of Aβ 1-42 on a broad set of parameters characteristic of AD: p-tau, neuroinflammation, vascular pathology, pyramidal cell survival, and behavior. Three days after Aβ 1-42 injection and

Impact of Two Neuronal Sigma-1 Receptor Modulators, PRE084 and DMT, on Neurogenesis and Neuroinflammation in an Aβ1–42-Injected, Wild-Type Mouse Model of AD

“…Regarding neuroinflammation, we found that a single administration of Aβ 1–42 stimulated neuroinflammatory processes, causing a significant increase in the densities of activated microglia and hyperreactive astrocytes. In line with our observations, several in vivo experiments have demonstrated the neuroinflammation-inducing effects of Aβ fibrils and oligomers injected into the brain tissue in different experimental models [ 93 , 94 , 95 ]. This neuroinflammatory environment may affect adult neurogenesis either positively or negatively [ 11 , 12 , 96 , 97 , 98 , 99 , 100 , 101 ].…”

Associations between diffusion MRI microstructure and cerebrospinal fluid markers of Alzheimer's disease pathology and neurodegeneration along the Alzheimer's disease continuum

“…Similarly, in a mostly preclinical cohort, pTau does not directly reflect the regional accumulation of neurofibrillary tangles and is probably, at least in part, indicative of a neuronal response to the deposition of β‐amyloid proteins. 13 , 52 As a result, it is likely that some of our DWI associations with pTau are artificially inflated by underlying amyloid pathology. Third, we did not consider the presence of WM hyperintensities (WMH) in our analysis.…”

Glutamatergic receptor expression changes in the Alzheimer's disease hippocampus and entorhinal cortex

“…We also report no acute Aβ 1‐42 ‐induced alteration in GluN2A subunit density within the mouse hippocampus ( 39 ), but chronic exposure resulted in downregulated subunit levels secondary to reduced neuronal labeling ( 31 ). In the mouse CA1 subregion 3‐days post‐Aβ 1‐42 injection astrogliosis is high and extended throughout the region, but at 3‐days post‐injection, increased GFAP density and astrocytes with activated morphology are localized to the injection site only ( 62 ). In the human CA1 subfield we did not detect GluN2A on neurons and the upregulation of GluN2A is associated with increased astrogliosis, the characteristic feature of AD and other neurodegenerative disorders ( 63 , 64 , 65 ), and increased expression of the subunit is localized to GFAP positive cells and processes.…”