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\begin{document}

\title{Of dolphins, humans, other long-lived animals and Alzheimer's disease
(Commentary on Vacher et al.)}



\author[1]{Guadalupe  Pereyra}%
\author[1]{Paola Bovolenta}%
\affil[1]{Universidad Autónoma de Madrid}%


\vspace{-1em}



  
  \date{May 29, 2024}


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\selectlanguage{english}
\begin{abstract}
Alzheimer's Disease (AD) is a familial or sporadic severe
neurodegenerative disorder that leads to short-term memory impairment
followed by progressive cognitive deterioration of executive functions.
AD frequency is increasing with a consequent socio-economic burden and
there is an urgent need to understand its aetiological complexity, find
reliable animal models and identify effective therapeutic treatments. AD
diagnosis relies on a series of neuropsychiatric criteria and the
detection of two pathognomonic protein aggregates in the brain
parenchyma: amyloid plaques and neurofibrillary tangles. The concurrence
of these aggregates seems to be mostly present in humans. In this issue,
Vacher and colleagues demonstrate the notable coexistence of AP
deposition and hyperphosphorylated tau in the brains of dolphins. Here
we discuss the relevance of this finding and how they could help
understanding AD%
\end{abstract}%



\sloppy


\textbf{Of dolphins, humans, other long-lived animals and Alzheimer's
disease}

\textbf{(Commentary on Vacher \emph{et al.})}

Guadalupe Pereyra\textsuperscript{1,2} and Paola
Bovolenta\textsuperscript{1,2}

\textsuperscript{1}Centro de Biolog\selectlanguage{ngerman}ía Molecular Severo Ochoa, CSIC-UAM,
c/ Nicolás Cabrera, 1, Campus de la Universidad Autónoma de Madrid,
Madrid 28049, Spain; \textsuperscript{2}CIBER de Enfermedades Raras
(CIBERER) Madrid 28049, Spain

Alzheimer's Disease (AD) is a familial or sporadic severe
neurodegenerative disorder that leads to short-term memory impairment
followed by progressive cognitive deterioration of executive functions.
Since its initial description in 1906 (Hippius \& Neundörfer, 2003), AD
has attracted increasing attention from basic neuroscientists,
clinicians, care givers and politicians not only for its increasing
frequency and socio-economic burden, but also for the still poorly
understood aetiological complexity of its most common sporadic form
(Knopman \emph{et al.} , 2021). This complexity precludes the generation
of reliable conventional animal models (e.g. mouse, rat) and the
existing ones, at best, resemble the identified genetic forms of AD.
Rodents do not develop spontaneous AD for a number of reasons (Drummond
\& Wisniewski, 2017) and, thus, the most commonly used AD-like mouse or
rat models are transgenic lines that express the mutated forms of human
genes (e.g. APP, PS1, PS2) present in patients suffering from familial
AD (Wu \emph{et al.} , 2012). These difficulties hamper understating AD
and the identification of effective therapeutic treatments, fostering
the quest for alternative means of research progress.

AD diagnosis relies on a series of neuropsychiatric criteria, the
analysis of cerebrospinal fluid (CSF) and the use of positron emission
tomography (PET) for the detection of two pathognomonic protein
aggregates in the brain parenchyma: amyloid plaques (AP), mainly
composed of aggregated A\selectlanguage{greek}β \selectlanguage{english}monomers, and neurofibrillary tangles (NFT)
containing hyperphosphorylated Tau (Wu \emph{et al.} , 2012). Aging is
the strongest risk factor for sporadic AD, suggesting that long-living
animals are potentially susceptible to developing spontaneous AD.
However, AD as such seems exclusively to be a human disease (Finch \&
Austad, 2015). Several animal species, including the great apes and
other nonhuman primates, which can have a relatively long lifespan, can
accumulate large amounts of A\selectlanguage{greek}β-\selectlanguage{english}positive APs and cerebral amyloid
angiopathy (CAA) as they age. They also show the presence of phospho-Tau
staining but there is little evidence for the accumulation of clear NFTs
or widespread brain degeneration (Drummond \& Wisniewski, 2017), which
characterise human AD. Similar APs or amyloid only accumulations have
been observed in other species with shorter lifespans (e.g. rhesus
macaque, vervets, lemurs and dogs) (Youssef \emph{et al.} , 2016;
Drummond \& Wisniewski, 2017). However, no evidence of AD-like protein
aggregates has been found in animals with life spans comparable to or
double that of humans, such as elephants (Cole \emph{et al.} , 1990) or
bowhead whales (Lagunas-Rangel, 2021), that are currently considered as
examples of ``healthy aging''. Furthermore, most animals do not show
signs of outright dementia as AD patients do (Drummond \& Wisniewski,
2017). In other words, the different animal species so far analysed do
not seem to suffer from bona fide AD (Table 1).

Somewhat surprisingly, in this issue, Vacher and colleagues demonstrate
the notable coexistence of AP deposition and hyperphosphorylated tau in
the brains of dolphins (Vacher \emph{et al.} , 2022), mammals that have
undergone considerable anatomical adaptations to their aquatic
environment, including in their brain organization. The authors analysed
brain samples from twenty-two dolphins of five different species, which
were found stranded along the Scottish coasts. They initially focused on
the limbic and anterior paralimbic lobes of the cerebral cortex that can
be compared to the brain areas in which protein aggregates initially
accumulate in AD patients. In three of the eighteen individuals with
recorded evidence of advanced age, they identified A\selectlanguage{greek}β-\selectlanguage{english}positive compact
and diffuse APs, vascular A\selectlanguage{greek}β \selectlanguage{english}accumulations suggestive of CAA as well as
phosphoTau-positive pre-NFTs (Table 1). These three cetaceans belonged
to three different species: \emph{Lagenorhynchus albirostris;
Globicephala melas} and \emph{Tursiops truncates} , all of which have an
A\selectlanguage{greek}β \selectlanguage{english}peptide amino acid sequence identical to that of humans, as also
observed in other mammals in which AP accumulation has been detected.
Analysis of additional brain regions from the same animals confirmed the
variable presence of both A\selectlanguage{greek}β \selectlanguage{english}and p-Tau aggregates, which were never
found in brain samples from younger animals of the same species.

The link between amyloid deposition and the formation of tau aggregates
in AD patients is still unclear. Nevertheless, longitudinal PET imaging
studies indicate that Tau accumulation precedes amyloid pathology,
whereas amyloid, once it has reached a threshold concentration, seems to
foster the spread of tau aggregates and neuronal death (rev in (Karran
\& De Strooper, 2022). Notably, Vacher \emph{et al.} (2022) found
abundant pTau-positive granules within neuronal cell bodies, axons and
dendrites as well as accumulations consistent with pre-NFT in additional
brain regions of the same individuals, where AP were either absent or
very sparse. PhosphoTau-immunolabelling consistent with intracellular
neuronal tangles was also found in an additional \emph{Globicephala
melas} in which APs were absent. Although rather speculative, these
observations suggest that dolphins may have a time course of formation
of pathological aggregates similar to that of humans, with phopho-Tau
accumulation preceding the presence of amyloid accumulation.

This does not mean that dolphins suffer from AD as this would be a
far-reaching conclusion in the absence of information related to
cognitive performance. Nevertheless, loss of the sense of direction or
similar disorientations (as observed in humans with initial mild
cognitive impairment) may explain mass strandings observed in some
dolphin species. Indeed, the ``sick leader'' hypothesis speculates that
members of a pod would also strand when following a leader with
cognitive decline. Furthermore, Vacher \emph{et al.} (2022) found only
mild evidence of reactive astrogliosis or activated microglia
surrounding the plaques, a characteristic that is common to AD
pathology, although this may again indicate that the brains analyzed
were at an early stage of AD-like pathology.

Independently of these considerations, this study shows the
susceptibility of odontocetes to develop spontaneous and concomitant
aggregates of APs and pre-NFT, the coexistence of which in humans has
been always associated with AD. There are previous reports describing
the presence of amyloid aggregates and a few neurofibrillary threads or
phosphor-tau-positive granules in the neurons of cetaceans' brains
(Gunn-Moore \emph{et al.} , 2018; Sacchini \emph{et al.} , 2020), but
Vacher \emph{et al.} (2022) are the first to establish a clear
correlation between the presence of APs and pTau aggregates with old age
and to identify accumulations that resemble NFTs. In an interesting
discussion, the authors review the idea that cetaceans possess some
physiological and behavioural traits that may make them a more accurate,
spontaneous model for studying AD than non-human primates. Besides being
relatively long-lived animals, some species of dolphins live in
cooperative groups and show care-giving behaviour towards diseased
individuals (Mead, 2023). This means that other dolphins within a pod
could help cognitively impaired individuals, compensating for abnormal
behaviour and thus allowing for the progression of neurodegenerative
pathologies. Supporting this possibility, Vacher \emph{et al.} (2022)
found no signs of AD-like pathology in harbour porpoises (\emph{Phocoena
phocoena} ), a relatively short-lived species of odontocete that lives
alone or in small groups, in line with the idea that free-ranging
animals with cognitive abnormalities are unlikely to survive in the
wild. Some odontocete species have been shown to have a relatively long
post-reproductive lifespan that in terrestrial animals is basically
limited to humans. How this trait can influence brain degeneration, as
suggested previously (Gunn-Moore \emph{et al.} , 2018), is not supported
or disproved in this study, but hormonal and related genetic changes may
be relevant.

Research in the AD field would benefit greatly from the identification
of a non-conventional animal model with spontaneous onset of the
disease. Practical and ethical considerations preclude the use of
cetaceans as such a possibility. Nevertheless, additional molecular and
behavioural research on aged odontocetes kept in captivity in zoos or
aquaria, and a more extensive analysis of samples such as those used in
this study may find additional commonalities with the human condition,
helping identifying additional important players in AD onset. There is a
long list of studies addressing the cellular profiles of AD brains (rev
in, Murdock \& Tsai, 2023) and recent proteomic studies in large cohorts
of AD patients point to interesting additional molecules that could be
relevant for AD pathogenesis (e.g. Johnson \emph{et al.} , 2022).
Dolphin brains could be subjected to similar analyses or at least
examined for the presence of similar candidate molecules, thereby
helping to understand their possible relevance. These are feasible
approaches that may offer new views and therapeutic avenues, both much
needed in the fight against neurodegenerative diseases.

\textbf{References}

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Drummond, E. \& Wisniewski, T. (2017) Alzheimer's disease: experimental
models and reality. \emph{Acta Neuropathol} , \textbf{133} , 155--175.

Edler, M.K., Sherwood, C.C., Meindl, R.S., Hopkins, W.D., Ely, J.J.,
Erwin, J.M., Mufson, E.J., Hof, P.R., \& Raghanti, M.A. (2017) Aged
chimpanzees exhibit pathologic hallmarks of Alzheimer's
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Finch, C.E. \& Austad, S.N. (2015) Commentary: is Alzheimer's disease
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Gunn-Moore, D., Kaidanovich-Beilin, O., Iradi, M.C.G., Gunn-Moore, F.,
\& Lovestone, S. (2018) Alzheimer's disease in humans and other animals:
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Hippius, H. \& Neund\selectlanguage{ngerman}örfer, G. (2003) The discovery of Alzheimer's
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Beach, T.G., Peng, J., De Jager, P.L., Haroutunian, V., Zhang, B.,
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Huttner, A.J., Dyck, C.H., Rosene, D.L., Nairn, A.C., \& Arnsten, A.F.T.
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\textbf{Table 1}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\textbf{Species} & \textbf{APs} & \textbf{CAA} & \textbf{p-Tau} &
\textbf{NFTs} & \textbf{RG} & \textbf{NeuroD} & \textbf{CD} &
\textbf{Reference}\tabularnewline
\midrule
\endhead
Humans & Y & Y & Y & Y & Y & Y & Y & (Hippius \emph{et al.}
2003)\tabularnewline
Dolphin & Y & Y & Y & Y & N & ND & ND & (Vacher \emph{et al.},
2022)\tabularnewline
Chimpanzee & Y & Y & Y & ? & ND & ND & ND & (Edler \emph{et al.},
2017)\tabularnewline
R. macaque & Y & Y & Y & ? & ND & ND & Y & (Paspalas \emph{et al.},
2018)\tabularnewline
Vervet & Y & Y & Y & N & Y & ND & ND & (Latimer \emph{et al.},
2019)\tabularnewline
Dog & Y & Y & Y & N & Y & ND & Y & (Schmidt \emph{et al.},
2015)\tabularnewline
\bottomrule
\end{longtable}

Presence of pathological signs associated with human AD in different
mammalian species. Aps, amyloid plaques; CAA, cerebral amyloid
angiopathy; CD, Cognitive deficit; NeuroD, neurodegeneration; NFTs,
neurofibrillary tangles; p-Tau, phosphor-Tau; RG, reactive gliosis. N,
NO; ND, non-determined; Y, yes; ? unclear.

\selectlanguage{english}
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