This article is mainly based on the author's keynote lecture titled ‘Vascular pathology in Alzheimer’s disease' at the 3rd World Congress on Vascular Factors in Alzheimer's Disease on 7–10 April 2002 in Kyoto, Japan, as well as on several presentations at other international conferences, including ‘Amyloid senile plaque and microvessels in the brain with Alzheimer’s disease', International Symposium on Dementia, Geneva, Switzerland, 1988; ‘Electron microscopy of amyloid fibrils and microvessels’, 1st Congress on Cardiovascular Pathology in Alzheimer's Disease, New York, USA, 1996; ‘Senile plaque formation in the brain with Alzheimer’s disease', International Psychiatric Symposium, Geneva, Switzerland, 1979; ‘The relationship between amyloid fibrils around cerebral blood vessels and senile plaques’, International Symposium on Dementia and Amyloid, Tokyo, Japan, 1985; ‘The role of blood vessels for producing pathological changes in the brain with Alzheimer’s disease', Vascular Factors in Alzheimer's Disease, Newcastle, UK, 1998; ‘Ultrastructural study of senile plaques and microvessels in the brain in Alzheimer’s disease', International Conference on Dementia, Angers, France, 1987; ‘Ultrastructural study of senile plaques and microvessels in the brain with Alzheimer’s disease and Down's syndrome', International Symposium on Dementia, Helsinki, Finland, 1988; ‘Ultrastructure of amyloid fibrils in the brain with Alzheimer’s disease and Down's syndrome', International Symposium on Alzheimer's disease, Tokyo, Japan, 1987; ‘Ultrastructure of neurofibrillary tangles in the brain with Alzheimer’s disease', International Symposium on Dementia, Niigata, Japan, 1989; ‘Ultrastructure of neurofibrillary tangles in the brain with Alzheimer’s disease', 11th International Congress of Neuropathology, Symposium on Aging and Dementia, Kyoto, Japan, 1980.
Histopathologically, numerous senile plaques and neurofibrillary tangles were remarkably observed in the brain with Alzheimer's disease. At the same time, so much simple atrophy of nerve cells was evident under light microscopy. Electron microscopical observations of serial sections revealed that small blood vessels, including capillaries, had a deep relationship to the amyloid fibrils which formed the senile plaques and they had fallen into degenerative states. The vascular feet of the astroglial cells surrounding small blood vessels showed degenerative features, and many nerve cells in this area either showed various degrees of degeneration or apparently were destroyed. The atrophy of the brain with Alzheimer's disease is considered to be caused by the amyloid angiopathy of small blood vessels and the degeneration of capillaries and vascular feet. These findings strongly suggest that the major causal mechanism of Alzheimer's disease is an alteration of the blood–brain barrier. Morphology is an expression of both the structure and the function of organs in the living body. Based on this viewpoint, this review article emphasizes that the morphological changes to small blood vessels in the brain with Alzheimer's disease convey crucial information and clues for solving the underlying mechanism that causes the disease.
Since Alois Alzheimer (1864–1915) first reported on a mental disorder case called Alzheimer's disease,1 a great deal of research has been carried out on the etiology of the disease in several different fields such as biochemistry,2,3 histopathology,4,5 brain imaging,6,7 epidemiology,8–12 and neuropsychology,13,14 as well as from the clinical aspects.15,16
Morphologically, the brain with Alzheimer's disease always shows severe atrophy. However, the exact mechanism of the cause of this characteristic atrophy still remains to be clearly determined with scientific accuracy. Thus, the histopathological changes which occur in the brain are of paramount importance and urgency in order to clearly elucidate the etiology of this incurable disease.
In this review article, I emphasize the major morphological developments of the brain with Alzheimer's disease as mainly understood and interpreted from the histopathological aspects.
The relationship between senile plaques and cerebral blood vessels
Scholz17 reported on the plaque-like degeneration of the arteries and capillaries and concluded that the core of senile plaques consisted of material which had permeated from the blood vessels. Other authors including Morel and Wildi,18 Pantelakis,19 and Corsellis and Brierlery20 have presented similar findings. Ishii21,22 also emphasized that senile plaques were related to blood vessels and capillaries, and he considered that the blood vessels had played the main role in the production of the plaques. Surbeck23 reported on ‘dyshoric angiopathy’ and demonstrated that plaque-like angiopathy follows senile plaques. After that, Mandybur24 reported findings on the correlation between the presence of ‘amyloidal-rich’ plaques and cerebral amyloidal angiopathy (especially the plaque-like angiopathy) but no apparent correlation with ‘amyloidal poor’ senile plaques or the neurofibrillary degeneration observed in Alzheimer's disease. Schote25 concluded that plaque-like angiopathy results from the infiltration of blood vessels by certain plasma proteins and electron micrographs of affected vessels revealed amyloidal fibrils arranged in the shape of ‘brush-like structures’ on the adventitial surface, a situation that can be taken to indicate the transmural flow of ‘precursor’ substances through the blood vessels into the cerebral parenchyma.
Miyakawa et al26 reported the presence of capillary plaque-like degeneration and asserted that senile plaques had an extremely close relationship to capillaries when examined with a scanning electron microscope.27 We suggested that each of the amyloidal fibrils which form the core of senile plaques are intimately connected with a capillary, and that several types of senile plaques seem to be the result of a primary change in the capillary involved in the formation of the amyloid fibrils.
To further clarify the relationship between senile plaques and capillary blood vessels, we carried out detailed morphological studies with both light and electron microscopy on several kinds of senile plaques which had been cut into fine serial sections for this purpose. Our findings revealed that every single senile plaque contained at least some amyloidal fibrils, and these appeared to have been produced at the basement membranes of the capillary endothelial cells and then somehow projected into the surrounding parenchyma. (Figs 1–3)
Even when a certain senile plaque seemed to be without any trace of the amyloidal fibril when looked at as an entity under light microscopy, the presence of at least one degenerable capillary containing some amyloid fibril was clearly demonstrable when the serial sections of the plaque were examined ultrastructurally.28 (Figs 4,5)
These repeatedly observed findings strongly suggest that the amyloid fibrils which form the core of several kinds of senile plaques are produced at the basement membrane of the endothelial cells. We speculate that the progressive degeneration of some capillaries ensuing from the formation of the amyloidal fibrils is the primary change in the emergence of senile plaques in the brain with Alzheimer's disease.
Following on these reports we presented several papers29–32 on detailed studies which concentrated mainly on the relationship between the blood vessels and amyloid fibrils that form the senile plaques peculiar to Alzheimer's disease.
In addition, we were the first to propose the ultrastructural model for the amyloid fibril33 and neurofibrillary tangles.34
Glenner35 reported that in a large proportion of cases of Alzheimer's presenile dementia, the major causal mechanism was an alteration of the blood–brain barrier resulting from the deposition of Congo-red-positive material in the walls of small blood vessels occurring in a relatively young age group. He concluded that a partially digested, filamentous protein (filarin) is further cleaved enzymatically by microglial cells to produce the amyloidal core of the neurite plaque.
In the brain with Alzheimer's disease, characteristic abnormal structures such as senile plaques and widespread neurofibrillary degeneration are commonly observed. At the same time, however, atrophy and neuronal loss are diffusely observed in the cerebral cortex in the brains of patients who have this degenerative and terminal disease.
Our research has mostly focused on the essence of the blood vessels that are evident in Alzheimer's disease.36–42 Observed under electron microscopy, invariably the results showed that the terminal arterioles and capillaries located in the areas of nerve cells had degenerated and some nerves had fallen into a degenerative state that included the loss of vascular feet (Figs 6,7). Particularly remarkable were those changes related to the capillaries. When small blood vessels were isolated from the brain cortex, they too showed a state of having undergone various degrees of degeneration.
As regards the severe atrophy of organic brain disease,43–45 histopathological findings could be observed as the change of capillaries including that of the vascular feet of astroglial cells in relation to the blood–brain barrier.
From the above-described findings directly connected with small blood degeneration, we consider that a deep casual relationship exists between the changes observed and the development of the amyloid fibril deposits that form the core of the senile plaques. As one important result of this relationship, the characteristic brain atrophy observed in the brain with Alzheimer's disease may also be regarded as an indication of some alteration of the small blood vessels having occurred, followed by progressive degeneration.
In the research concentrating on trying to solve the mechanism of senile plaque production in the brain with Alzheimer's disease, so far there have been many reports proposing a different pathogenesis to that from a blood vessel origin.
Teilum's46 suggestion that the generalized amyloidal fibril deposition could be from reticular cells led some researchers to believe that the amyloidal fibrils in the brain may be produced by glial cells. Terry et al47 regarded amyloid deposition which forms senile plaques as being a secondary reaction following a primary degeneration of nerve cells. The exact source of the amyloid remained uncertain, however, but it appeared that it was a local cellular product rather than coming from the blood. Wisniewski et al48 reported that the neurite plaques were composed of degenerative neural terminals and concluded that the origin of the classic plaque lies in the degeneration of neurites which precede the deposition of amyloid. They also reported49 the amyloid-associated cells observed under light and electron microscopy to be reactive microglial cells.
Genetically, in 1995, Games et al50 succeeded in making an animal model which produces amyloid deposition in the brain by using a neuro-specific promoter which drives human amyloid precursor protein (APP). From their observations, they concluded that the deposition in the parenchyma precedes the deposition of vascular amyloid. Since then, the neuron origin of the amyloid production in the brain with Alzheimer's disease has been favored by many researchers.
However, in the human brain with Alzheimer's disease, the amyloid fibrils which form the senile plaques were mainly located around the capillaries when observed under electron microscopy.
As I described above, in detailed examination of serial sections with both light and electron microscopy, destroyed capillaries with amyloid fibrils could be found in every single plaque. In our detailed experiments, we repeatedly encountered the difficulty of recognizing severely damaged capillaries as capillary structures. It is a very difficult endeavor unless detailed electron microscopical examinations of many serial sections of the same specimen are performed. Without doing such experiments, the impression might be formed that many senile plaques bear no relation to the capillaries.
Histochemically, Katenkamp et al51 reported that the amyloid observed in the brain was of the γ-globulin type and Zucker-Franklin and Franklin52 suggested that the amyloid might be synthesized through the surface-associated enzyme system of blood monocytes. Recently, Seth et al53 reported that APOE epsin 4 is a major risk factor for cerebral amyloid angiopathy and affects most patients with Alzheimer's disease. Recent epidemiological studies by Nakajima12 have reported findings suggesting a possible relationship between psychiatric symptoms and cerebral blood flow. These findings might be related to the disturbance of the microvessls' circulation observed in the brain of Alzheimer's disease patients.
In conclusion, I want to emphasize that the microvessel origin of the amyloid fibrils which form senile plaques (capillary angiopathy) is highly plausible based on the empiric evidence obtained until now. Furthermore, I expect that the exact mechanism of the amyloid production will also be clearly established through further biochemical research in the not too distant future.