Chronic Basal Forebrain Activation Improves Spatial Memory, Boosts Neurotrophin Receptor Expression, and Lowers BACE1 and Aβ42 Levels in the Cerebral Cortex in Mice

Authors

Jacob Kumro
Ashutosh Tripathi
Yun Lei
Jeremy Sword
Patrick Callahan
Alvin Terry
Xin-Yun Lu
Sergei A Kirov
Anilkumar Pillai
David T Blake

Publication Date

6-8-2023

Journal

Cerebral Cortex

Abstract

The etiology of Alzheimer’s dementia has been hypothesized in terms of basal forebrain cholinergic decline, and in terms of reflecting beta-amyloid neuropathology. To study these different biological elements, we activated the basal forebrain in 5xFAD Alzheimer’s model mice and littermates. Mice received 5 months of 1 h per day intermittent stimulation of the basal forebrain, which includes cholinergic projections to the cortical mantle. Then, mice were behaviorally tested followed by tissue analysis. The 5xFAD mice performed worse in water-maze testing than littermates. Stimulated groups learned the water maze better than unstimulated groups. Stimulated groups had 2–3-fold increases in frontal cortex immunoblot measures of the neurotrophin receptors for nerve growth factor and brain-derived neurotrophic factor, and a more than 50% decrease in the expression of amyloid cleavage enzyme BACE1. Stimulation also led to lower Aβ42 in 5xFAD mice. These data support a causal relationship between basal forebrain activation and both neurotrophin activation and reduced Aβ42 generation and accumulation. The observation that basal forebrain activation suppresses Aβ42 accumulation, combined with the known high-affinity antagonism of nicotinic receptors by Aβ42, documents bidirectional antagonism between acetylcholine and Aβ42.

Keywords

Alzheimer’s, neurotrophin, acetylcholine, deep brain stimulation

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Supplementary Materials

PMID: 36939283