Thanks, very good link.

Quote:

---

Before the onset of Aβ plaque deposition and cognitive impairment, 5XFAD mice have exhibited abnormalities in sharp wave ripple (SWR)-related slow gamma oscillations (10–50 Hz)

---

So there is something that precedes the cognitive decline and plaque accumulation that affects SWRs. I believe that to be inflammatory factors.

Quote:

---

The appearance of hippocampal sharp wave ripples (SWRs) is an electrophysiological biomarker for episodic memory encoding and behavioral planning. Disturbed SWRs are considered a sign of neural network dysfunction that may provide insights into the structural connectivity changes associated with cognitive impairment in early-stage Alzheimer's disease (AD) and temporal lobe epilepsy (TLE).

Understanding how SWR disruption impairs memory function, especially episodic memory, could aid in the development of more efficacious therapeutics for AD and TLE.

For instance, the hyperexcitability associated with seizures may disrupt neural network connectivity, thereby increasing plaque burden. Moreover, memory impairment is also a major sequela of temporal lobe seizures. The hippocampus, a structure within the medial temporal lobe, is critical for encoding events as transferable units of experience and for the consolidation of these experiences into long-term memories. These processes are mediated by the formation of neuronal ensembles that fire in specific contexts, such as the location-specific hippocampal place cells observed following spatial navigation learning. It is believed that ensemble formation is mediated in part by use-dependent synaptic plasticity, such as NMDA receptor (NMDAR)-dependent long-term potentiation (LTP), initiated by oscillatory brain activity (rhythms) and regulated by a variety of neuromodulators such as brain-derived neurotrophic factor (BDNF), dopamine, and acetylcholine (ACh). These oscillations effectively enable both the formation and consolidation of memories through repeated circuit activation in the days and nights following learning events.
https://www.frontiersin.org/articles/10.3389/...83483/full

---

CCR5 blockade stops the loss due to inflammation of the NMDA receptor subunit 1 (NMDA receptor subunit one is a necessary component of NMDA). Blockade upregulates BDNF. Blockade downregulates acetycholine which corrects an imbalance that effects neural transmission.