Deadly combination in neurodegenerative diseases revealed

November 13, 2017
Degenerating interneurons in frontotemporal lobar degeneration (FTLD) mice. (a) Poly-ubiquitin positive protein aggregates (arrows) in the hippocampus of aged FTLD mice (TDP-43 transgenic mice). (b) Immunofluorescence staining show these aggregates contain p62 and parvalbumin, a marker of interneurons (arrows). (c) Staining by parvalbumin antibody show intact (arrowheads) and degenerating interneurons (arrows) in the hippocampus of aged FTLD mice. Credit: Nagoya University

Neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration and death of nerve cells, which leads to problems with movement or mental functioning. Examples include Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is characterized by degeneration of motor neurons, while FTD is characterized by progressive neuronal loss mostly in the frontal and/or temporal lobes of the brain.

Neurodegenerative diseases are increasingly being realized to have common cellular and molecular mechanisms including protein misfolding and aggregation. In nearly half of all FTD cases and in 97% of the ALS cases, there is an accumulation of the protein TDP-43 in the affected neurons, the basic working units of the nervous system.

In a non-disease state, TDP-43 is an important protein involved in various aspects of the metabolism of RNA, a molecule essential in various biological roles in the regulation and expression of genes. In a disease state, several mutations in TDP-43 have been identified as a cause of some hereditary and sporadic ALS and FTD cases. While this underscores the critical role of TDP-43 in the development of these conditions, the specific effect of aging on TDP-43 has not been investigated. This prompted a team of scientists centered in Nagoya, Japan, to delve deep into the subject. Their findings were recently published in Scientific Reports.

For their investigation, the researchers first developed a disease model of transgenic mice expressing elevated levels of TDP-43 to capture the pathology of sporadic ALS/FTD. They then performed serial behavioral tests on the mice, including Y-maze test (to assess working memory), rotarod test (motor function and learning), and contextual and cued fear condition test (fear learning and memory).

"In expressing unusually high levels of TDP-43 we observed memory and motor deficits," study corresponding author Koji Yamanaka says. "We also noticed an accumulation of debris of interneurons – the cells that serve as a connection between sensory and motor pathways for reflexes – in the hippocampus, which is responsible for memory storage."

Notably, the abundance of aggregates drastically increased with age and with the overexpression of TDP-43. Gene analyses of the hippocampus and other brain areas revealed dysregulation in the genes linked to manifestation of damaging reactive oxygen species and neuronal function.

"The degeneration of interneurons as seen in our mouse model could be the very early age-accelerated changes observed in the diseases," Yamanaka says. "Moreover, it has been reported that inhibitory interneuron deficits link altered network activity and cognitive dysfunction in models of Alzheimer's . Therefore, this particular mouse model may be useful for studying neurological diseases accelerated by aging."

Explore further: Mechanism explains how seizures may lead to memory loss

More information: Hitomi Tsuiji et al. TDP-43 accelerates age-dependent degeneration of interneurons, Scientific Reports (2017). DOI: 10.1038/s41598-017-14966-w

Related Stories

Mechanism explains how seizures may lead to memory loss

October 16, 2017
Although it's been clear that seizures are linked to memory loss and other cognitive deficits in patients with Alzheimer's disease, how this happens has been puzzling. In a study published in the journal Nature Medicine, ...

Researchers reveal unusual chemistry of protein with role in neurodegenerative disorders

July 27, 2017
A common feature of neurodegenerative diseases is the formation of permanent tangles of insoluble proteins in cells. The beta-amyloid plaques found in people with Alzheimer's disease and the inclusion bodies in motor neurons ...

Link identified between nerve cell proteins and middle-age onset dementia

February 13, 2017
Nagoya University-led research identifies role for neuronal protein interaction in preventing frontotemporal lobar degeneration, a dementia that starts in middle age.

Study highlights gene that could lead to therapies for Amyotrophic Lateral Sclerosis

October 4, 2016
Researchers from Ben-Gurion University of the Negev (BGU) have published a new study that describes a novel molecular mechanism that could lead to the development of new therapies for Amyotrophic Lateral Sclerosis (ALS). ...

New research points to potential treatment for memory loss activating a protein dysregulated in dementia

January 31, 2017
A new study, published on the cover of the scientific journal Biological Psychiatry and lead by Dr Carlos Saura from the Institut de Neurociències (INc) at the Universitat Autònoma de Barcelona (UAB), reveals a new molecular ...

New molecular discovery may help identify drug therapies to prevent dementia

January 10, 2017
Rutgers University scientists have discovered a molecular pathway in the brain that may help provide answers to long-term memory problems in the elderly and aid researchers in identifying drug-based therapies to prevent dementia.

Recommended for you

Small but distinct differences among species mark evolution of human brain

November 23, 2017
The most dramatic divergence between humans and other primates can be found in the brain, the primary organ that gives our species its identity.

Team constructs whole-brain map of electrical connections key to forming memories

November 22, 2017
A team of neuroscientists at the University of Pennsylvania has constructed the first whole-brain map of electrical connectivity in the brain based on data from nearly 300 neurosurgical patients with electrodes implanted ...

To forget or to remember? Memory depends on subtle brain signals, scientists find

November 22, 2017
The fragrance of hot pumpkin pie can bring back pleasant memories of holidays past, while the scent of an antiseptic hospital room may cause a shudder. The power of odors to activate memories both pleasing and aversive exists ...

Pitch imperfect? How the brain decodes pitch may improve cochlear implants

November 22, 2017
Picture yourself with a friend in a crowded restaurant. The din of other diners, the clattering of dishes, the muffled notes of background music, the voice of your friend, not to mention your own – all compete for your ...

New research suggests high-intensity exercise boosts memory

November 22, 2017
The health advantages of high-intensity exercise are widely known but new research from McMaster University points to another major benefit: better memory.

Schizophrenia originates early in pregnancy, 'mini-brain' research suggests

November 20, 2017
Symptoms of schizophrenia usually appear in adolescence or young adulthood, but new research reveals that the brain disease likely begins very early in development, toward the end of the first trimester of pregnancy. The ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.