Alzheimer's Disease Genetic Risk Factor APOE-ε4 Also Affects Normal Brain Function

AbstractThe E4 allele of apolipoprotein E (apoE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). However, apoE4 may cause innate brain abnormalities before the appearance of AD related neuropathology. Understanding these primary dysfunctions is vital for early detection of AD and the development of therapeutic strategies for it. Recently we have shown impaired extra-hippocampal memory in young apoE4 mice – a deficit that was correlated with attenuated structural pre-synaptic plasticity in cortical and subcortical regions. Here we test the hypothesis that these early structural deficits impact learning via changes in basal and stimuli evoked neuronal activity. We recorded extracellular neuronal activity from the gustatory cortex (GC) of three-month-old humanized apoE4 and wildtype rats, before and after conditioned taste aversion (CTA) training. Despite normal sucrose drinking behavior before CTA, young apoE4 rats showed impaired CTA learning, consistent with our previous results in apoE4 mice. This behavioral deficit was correlated with decreased basal and taste-evoked firing rates in both putative excitatory and inhibitory GC neurons. Single neuron and ensemble analyses of taste coding demonstrated that apoE4 neurons could be used to correctly classify tastes, but were unable to undergo plasticity to support learning. Our results suggest that apoE4 impacts brain excitability and plasticity early in life and may act as an initiator for later AD pathologies.Significant statementThe ApoE4 allele is the strongest genetic risk-factor for late-onset Alzheimer’s disease (AD), yet the link between apoE4 and AD is still unclear. Recent molecular and in-vitro studies suggest that apoE4 interferes with normal brain functions decades before the development of its related AD neuropathology. Here we recorded the activity of cortical neurons from young apoE4 rats during extra-hippocampal learning to study early apoE4 neuronal activity abnormalities, and their effects over coding capacities. We show that apoE4 drastically reduces basal and stimuli-evoked cortical activity in both excitatory and inhibitory neurons. The apoE4-induced activity attenuation did not prevent coding of stimuli identity and valence, but impaired capacity to undergo activity changes to support learning. Our findings support the hypothesis that apoE4 interfere with normal neuronal plasticity early in life; a deficit that may lead to late-onset AD development.

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Amyloid β-Peptide and Central Cholinergic Neurons: Involvement in Normal Brain Function and Alzheimer’s Disease Pathology

Abeta Peptide and Alzheimer’s Disease ◽

10.1007/978-1-84628-440-3_10 ◽

2006 ◽

pp. 159-178

Author(s):

Satyabrata Karn ◽

Z. Wei ◽

David MacTavish ◽

Doreen Kabogo ◽

Mee-Sook Song ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Function ◽

Amyloid Β ◽

Cholinergic Neurons ◽

Normal Brain ◽

Amyloid Β Peptide ◽

Normal Brain Function

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Ozone and Particulate Matter Exposure and Alzheimer’s Disease: A Review of Human and Animal Studies

Advances in Alzheimer’s Disease - Alzheimer’s Disease and Air Pollution ◽

10.3233/aiad210034 ◽

2021 ◽

Author(s):

Rui-Ming Liu ◽

Zechen Chong ◽

Jiu-Chiuan Chen

Keyword(s):

Alzheimer’S Disease ◽

Risk Factor ◽

Particulate Matter ◽

Environmental Exposure ◽

Environmental Risk ◽

Genetic Risk ◽

The Elderly ◽

Genetic Risk Factor ◽

Apoe Ε4 ◽

Particulate Matter Exposure

Alzheimer’s disease (AD), an aging-related neurodegenerative disease, is a major cause of dementia in the elderly. Although the early-onset (familial) AD is attributed to mutations in the genes coding for amyloid-β protein precursor (AβPP) and presenilin 1/presenilin 2 (PS1/PS2), the cause for the late-onset AD (LOAD), which accounts for more than 95% of AD cases, remains unclear. Aging is the greatest risk factor for LOAD, whereas the apolipo protein E4 allele (APOEε4) is believed to be a major genetic risk factor in acquiring LOAD, with female APOE ε4 carriers at highest risk. Nonetheless, not all the elderly, even older female APOE ε4 carriers, develop LOAD, suggesting that other factors, including environmental exposure, must play a role. This review summarizes recent studies that show a potential role of environmental exposure, especially ozone and particulate matter exposure, in the development of AD. Interactions between environmental exposure, genetic risk factor (APOE ε4), and sex in AD pathophysiology are also discussed briefly. Identification of environmental risk factor(s) and elucidation of the complex interactions between genetic and environmental risk factors plus aging and female sex in the onset of AD will be a key to our understanding of the etiology and pathogenesis of AD and the development of the strategies for its prevention and treatment.

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