Cite this article: Busche MA, Konnerth A.
2016 Impairments of neural circuit function
in Alzheimer’s disease. Phil. Trans. R. Soc. B
Accepted: 31 March 2016
One contribution of 15 to a Theo Murphy
meeting issue ‘Evolution brings Ca
ATP together to control life and death’.
Alzheimer’s disease, amyloid-b,in vivo
calcium imaging, mouse models
Authors for correspondence:
Marc Aurel Busche
Impairments of neural circuit function
in Alzheimer’s disease
Marc Aurel Busche1,2,3,4 and Arthur Konnerth1,3,4
Institute of Neuroscience, and
Department of Psychiatry and Psychotherapy, Technical University of Munich,
Munich Cluster for Systems Neurology (SyNergy), and
Center of Integrated Protein Science Munich (CIPSM),
An essential feature of Alzheimer’s disease (AD) is the accumulation of amy-
loid-b(Ab) peptides in the brain, many years to decades before the onset of
overt cognitive symptoms. We suggest that during this very extended early
phase of the disease, soluble Aboligomers and amyloid plaques alter the
function of local neuronal circuits and large-scale networks by disrupting
the balance of synaptic excitation and inhibition (E/Ibalance) in the brain.
The analysis of mouse models of AD revealed that an Ab-induced change
of the E/Ibalance caused hyperactivity in cortical and hippocampal neurons,
a breakdown of slow-wave oscillations, as well as network hypersynchrony.
Remarkably, hyperactivity of hippocampal neurons precedes amyloid
plaque formation, suggesting that hyperactivity is one of the earliest dys-
functions in the pathophysiological cascade initiated by abnormal Ab
accumulation. Therapeutics that correct the E/Ibalance in early AD may pre-
vent neuronal dysfunction, widespread cell loss and cognitive impairments
associated with later stages of the disease.
This article is part of the themed issue ‘Evolution brings Ca
together to control life and death’.
Alzheimer’s disease (AD) is the most common cause of intellectual decline in
the elderly population worldwide . AD is characterized by slowly progres-
sive memory deficits, cognitive impairments and dementia. The diagnosis is
established by these clinical features combined with biomarker evidence for
amyloid-b(Ab) accumulation (as measured by cerebrospinal fluid (CSF) levels
or positron emission tomography (PET)-amyloid imaging) and/or neur-
onal degeneration (as measured by CSF levels of tau and phosphorylated tau as
well as fluorodeoxyglucose (FDG)-PET or structural magnetic resonance imaging
(MRI)) in the brain . Current treatments are unsatisfactory as they provide only
symptomatic relief and are effective in only a subset of affected individuals .
It is becoming increasingly clear that the pathogenic cascade that causes AD
begins decades before first clinical symptoms become evident [4,5]. For instance,
in people at risk of AD abnormal Abaccumulation and amyloid deposition, as
measured by CSF
and amyloid-PET, was detected 25 years before symptom
onset . There is growing evidence from functional MRI (fMRI) that this ‘precli-
nical’ stage of AD is associated with profound functional alterations of brain
networks that seem to be structurally largely intact. For example, hippocampal
hyperactivation and impaired deactivation of the default-mode network during
memory-encoding have been demonstrated in people at genetic risk for AD
[7–9], cognitively normal individuals with evidence for Abaccumulation
[10– 12] and people with early AD [13–15].
Major unresolved issues include the questions of why neuronal circuits
become dysfunctional in response to high Ablevels and how circuit abnormal-
ities can be repaired. As these problems cannot be studied easily in humans
with existing techniques, transgenic mouse models overproducing human
mutant Abare in many cases the method of choice for such investigations.
Indeed, recent experimental evidence obtained in mouse model studies suggest
&2016 The Author(s) Published by the Royal Society. All rights reserved.