Impairments of spatial memory in an Alzheimer’s disease model via degeneration of hippocampal cholinergic synapses

Abstract

Choline acetyltransferase neurons in the vertical diagonal band of Broca (vChATs) degenerate in the early stage of Alzheimer’s disease (AD). Here, we report that vChATs directly innervate newly generated immature neurons (NGIs) in the dorsal hippocampus (dNGIs) of adult mice and regulate both the dNGIs survival and spatial pattern separation. In a mouse model that exhibits amyloid-β plaques similar to AD patients, cholinergic synaptic transmission, dNGI survival and spatial pattern separation are impaired. Activation of vChATs with theta burst stimulation (TBS) that alleviates the decay in cholinergic synaptic transmission effectively protects against spatial pattern separation impairments in the AD mice and this protection was completely abolished by inhibiting the dNGIs survival. Thus, the impairments of pattern separation-associated spatial memory in AD mice are in part caused by degeneration of cholinergic synaptic transmission that modulates the dNGIs survival.

Mossy cell synaptic dysfunction causes memory imprecision via miR‐128 inhibition of STIM2 in Alzheimer's disease mouse model

“…There are two major pathological hallmarks, including extracellular deposition of amyloid‐β (Aβ) plaques and intracellular aggregates of abnormal tau protein tangles that are seen in the brain of AD patients and have long been considered to be the causes of neuronal degeneration and memory loss (Duffy et al, 2015; Lazarov et al, 2005; Ohno et al, 2004; Vassar, 2007). However, recent studies indicate that memory loss is caused by synaptic dysfunction rather than neuronal death (Hsia et al, 1999; Ittner et al, 2010; Jacobsen et al, 2006; Selkoe, 2002; Shu et al, 2016; X. Yang et al, 2018; Zhu et al, 2017).…”

Evidence of altered depression and dementia‐related proteins in the brains of young rats after ovariectomy

“…After the FST, all rats underwent a 6-day training period of spatial learning in the Morris water maze as previously described (Zhu et al 2017). We filled a 1.8 meter-diameter swimming pool with black, non-toxic ink water.…”

Neuroprotective Effects of Choline and Other Methyl Donors

“…These molecular changes correlated with a decrease in the levels of the stress hormone cortisol in the cord blood [45]. Changes in choline levels have also been associated with alteration in cognitive functions with aging [46,47], Alzheimer's disease (AD) [48,49], behavioral changes in animal model of prenatal alcohol exposure [17,[50][51][52], and with symptoms of neurodevelopmental disorders such as Rett Syndrome [26,53] and Down Syndrome [25,54,55].…”

“…This reduction of choline uptake by the aging brain would then induce degradation of PC in neuronal membranes as a compensatory mechanism to keep up with brain demand of choline for Ach synthesis [90]. The reduction of choline with aging has been linked to the degeneration of membrane phospholipids in neurodegenerative disorders and loss or decrease in cholinergic neurons activity in affected brain regions [48,49]. Thus, choline supplementation with other methyl-donors in the elderly or with patients at early stages of AD may contribute to the increase of choline uptake by the aging brain and increase choline levels for Ach synthesis.…”